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Identification of Electrostatic Hotspots at the Binding Interface of Amylin and Insulin-Degrading Enzyme: A Structural and Biophysical Investigation

This version is not peer-reviewed.

Wei Li  *

Submitted:

01 February 2024

Posted:

01 February 2024

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Abstract
Amylin, also known as islet amyloid polypeptide (IAPP), is a metabolic homeostasis-related hormone that is produced and released by the β cells of the pancreas, the same cells that produce insulin. Insulin-degrading enzyme (IDE) is a protease enzyme that plays an essential role in the breakdown and degradation of various peptides, including insulin and amylin. Direct binding & interaction between amylin and IDE is inextricably linked to the degradation of amylin, and research and development effort in this area is crucial to understand the potential therapeutic implications of disrupting the IDE-amylin interaction in the context of conditions where metabolic homeostasis needs to be regulated, such as diabetes and obesity. Here, this article incorporates currently available experimental complex structure of amylin and IDE, and delves deep into the interstructural biophysics underlying the binding interface of the two interacting partners. With a set of comprehensive structural biophysical analysis, this article identified an intriguing region of high electrostatic potential indicative of strong binding sites between the first N-terminal lysine (Lys1, K1) residue of amylin and Glu341 (E341) of IDE. This unique electrostatic hotspot presented herein paves the way for the rational design of drug-like small molecules that can selectively disrupt this interaction, offering a targeted therapeutic strategy for improved metabolic homeostasis, particularly for patients with diabetes and obesity.
Keywords: 
Amylin; Insulin-degrading enzyme; Electrostatic hotspots; Salt bridge; Hydrogen bond
Subject: 
Biology and Life Sciences  -   Biophysics

1. Introduction

Amylin is a 37-amino-acid pancreatic hormone acting to control energy homeostasis and body weight [1,2,3,4]. Physiologically, amylin regulates glucose homeostasis by inhibiting insulin and glucagon secretion [5,6,7]. Furthermore, amylin modulates satiety and inhibits gastric emptying via the central nervous system [8,9,10,11]. Produced and released by pancreatic cells, amylin shares a common secretion pathway with insulin, collectively orchestrating the postprandial control of glucose homeostasis [12,13,14,15]. The intricate regulatory network governing blood sugar levels involves a delicate interplay between hormones and enzymes, among which amylin (islet amyloid polypeptide, IAPP) and insulin-degrading enzyme (IDE) stand as key players [12,16,17,18,19,20,21], where IDE plays a crucial role in the degradation and clearance of amylin from the bloodstream [22,23,24]. The cooperation between amylin and IDE, therefore, is pivotal in maintaining the delicate balance of glucose homeostasis and averting the detrimental consequences of amyloid deposition [25,26,27,28,29]. For instance, IDE defects are linked to the development of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) [13,18,30].

2. Motivation

Thanks to the continued development of experimental structural biology and the half-a-century old Protein Data Bank (PDB) [31,32], a comprehensive structural biophysical (CSB) analysis becomes possible [33,34,35] for specific ligand-receptor [36,37,38], antigen-antibody [39] or enzyme-substrate [40,41,42] complex structures deposited in PDB, expanding our understanding of the structural and biophysical basis of their interfacial structural stability, and facilitating the design of drug analogues with improved affinity to their interacting partners [43,44].
As a matter of fact, structural and biochemical analyses [45,46,47,48] have already revealed the binding mode and pattern for the formation of the IDE-amylin complex structure, and this experimental information is useful but insufficient for the development of promising inhibitors (e.g., small molecules) of IDE-amylin interaction to improve glucose homeostasis. This manuscript, therefore, seeks to delve into the structural and biophysical aspects of the interaction between amylin and IDE, with a specific focus on identifying electrostatic hotspots at their binding interface. In case these hotspots are able to act as potential binding sites for drug-like small molecules, the aim of this article is to provide a precise and targeted approach for the development of small molecules to disrupt the amylin-IDE interaction.

3. Materials and Methods

As of February 1, 2024, a total of 101 experimental structures have been deposited in Protein Data Bank (PDB) [31] as listed in Table 1, according to a text query: QUERY: Full Text = "amylin" of the Protein Data Bank (PDB) [31]. Among them, only two experimental structures represent the amylin-IDE complex, with PDB IDs: 2G48 [45,46] and 3HGZ [47,48], respectively, providing an accurate structural basis of the IDE-amylin interaction specificity for subsequent comprehensive structural biophysical (CSB) analysis of the two structural models (two yellow rows in Table 1).
First, after the atomic coordinates file for PDB IDs: 2G48 [45,46] and 3HGZ [47,48] were downloaded from the PDB [31] website, Chimera [49] was employed to manually add hydrogen atoms to the structural model of the two structural models representing IDE-amylin complex. Afterwards, the two hydrogen-added structural models were subject to a set of comprehensive structural biophysical (CSB) analysis as described in [33] to identify key residue-specific interactions at the amylin-IDE binding interface and uncover the interstructural biophysics underlying the IDE-amylin complex structure.
Specifically, the CSB analysis here [33] consists of the structural identification of salt bridges and side chain hydrogen bonds at the binding interface of amylin and IDE. Given the fact that native proteins are in dynamic equilibrium with their less-structured, partially folded and/or unfolded states [50], and that, according to an NMR structure of human amylin bound to model membranes, the helix structure of amylin itself is also dynamic, this article uses two sets of screening criteria for the structural identification of potential hotspots at the IDE-amylin binding interface in the two structural models i.e., PDB IDs: 2G48 [45,46] and 3HGZ [47,48].
First, the same set of criteria as in [33] was used, i.e., the interfacial salt bridge analysis was conducted with an in-house python script only for titrateable residues (Asp, Glu, Lys, Arg and His), 4.0 Å was used as the cutoff distance for the two oppositely charged groups [33,51]. The hydrogen bond analysis was also conducted for only side chain nuclei with an in-house python script, and employed two geometric criteria: (a) a cutoff value of the angle formed by acceptor (A), donor (D) and hydrogen (H) ( A D H ) of 30; (b) a cutoff value of donor-acceptor distance at 3.0 Å. That is, a hydrogen bond is only considered to be formed if A D H is not larger than 30 and the donor-acceptor distance is not larger than 3.0 Å [33,51].
Afterwards, a new set of criteria was used to account for the dynamic -helix structure of amylin itself, i.e., the interfacial salt bridge analysis was conducted with an in-house python script only for titrateable residues (Asp, Glu, Lys, Arg and His), 6.0 Å was used as the cutoff distance for the two oppositely charged groups [33,51]. The hydrogen bond analysis was also conducted for only side chain nuclei with an in-house python script, and employed two geometric criteria: (a) a cutoff value of the angle formed by acceptor (A), donor (D) and hydrogen (H) ( A D H ) of 50; (b) a cutoff value of donor-acceptor distance at 5.0 Å. That is, a hydrogen bond is only considered to be formed if A D H is not larger than 30 and the donor-acceptor distance is not larger than 5.0 Å [33,51].
Here, the in-house python scripts essentially are the same as those used in [52], except for the differences in three key parameters related to the screening criteria, i.e., the salt bridge distance cutoff in Å, cutoff angle A D H in for hydrogen bonding, and the cutoff distance (in Å) of donor-acceptor for hydrogen bonding.

4. Results

4.1. Characterization of residue-specific electrostatic interactions at the amylin-IDE binding interface

As of February 1, 2024, there are only two experimental structures representing the amylin-IDE complex, with PDB IDs: 2G48 [45,46] and 3HGZ [47,48], respectively (Table 1). As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively. For the two structural models (2G48 [45,46] and 3HGZ [47,48]), this article reports a set of comprehensive structural biophysical (CSB) analysis as described in [33], which lead to a set of residue-specific electrostatic interactions at the binding interface of amylin-IDE, as listed in Table 2, Table 3, Table 4, Table 5, Table 6 and Table 7. Specifically,
  • 10 interfacial salt bridges (Table 2) were structurally identified for the amylin-IDE complex structure PDB ID 2G48 [45,46], according to the old set of criteria as in [33].
  • of the 10, only 1 interfacial salt bridge (Table 2) was structurally identified at the amylin-IDE binding interface for the amylin-IDE complex structure PDB ID 2G48 [45,46], according to the old set of criteria as in [33].
  • 6 interfacial salt bridges (Table 2) were structurally identified for the amylin-IDE complex structure PDB ID 3HGZ [47,48], according to the old set of criteria as in [33].
  • of the 6, 2 interfacial salt bridges (Table 2) were structurally identified at the amylin-IDE binding interface for the amylin-IDE complex structure PDB ID 3HGZ [47,48], according to the old set of criteria as in [33].
  • 14 interfacial side chain and main chain hydrogen bonds (Table 3) were structurally identified for the amylin-IDE complex structure PDB ID 2G48 [45,46], according to the old set of criteria as in [33].
  • no interfacial side chain or main chain hydrogen bond was structurally identified for the amylin-IDE complex structure PDB ID 3HGZ [47,48], according to the old set of criteria as in [33].
  • 4 interfacial side chain hydrogen bonds (Table 4) were structurally identified for the amylin-IDE complex structure PDB ID 2G48 [45,46], according to the old set of criteria as in [33].
  • no interfacial side chain was structurally identified for the amylin-IDE complex structure PDB ID 3HGZ [47,48], according to the old set of criteria as in [33].
As discussed above, to account for the dynamic helix structure and less-structured or random coil region of amylin, this article uses two sets of screening criteria for structural identification of potential electrostatic hotspots at the IDE-amylin binding interface in the two structural models i.e., PDB IDs: 2G48 [45,46] and 3HGZ [47,48]. Specifically,
  • a total of 22 interfacial salt bridges (Table 5) were structurally identified for the amylin-IDE complex structure PDB ID 2G48 [45,46], according to a new set of criteria [33] as defined in the section of Materials and Methods.
  • among the 22, only 3 interfacial salt bridges (Table 5) were structurally identified between Lys1 and Glu341 (Figure 2 and Figure 3) at the binding interface of IDE and amylin for the amylin-IDE complex structure PDB ID 2G48 [45,46], according to a new set of criteria [33] as defined in the section of Materials and Methods.
  • a total of 16 interfacial salt bridges (Table 5) were structurally identified for the amylin-IDE complex structure PDB ID 3HGZ [47,48], according to a new set of criteria [33] as defined in the section of Materials and Methods.
  • among the 16, only 4 interfacial salt bridges (Table 5) were structurally identified between Lys1 and Glu341 (Figure 2 and Figure 3) at the binding interface of IDE and amylin for the amylin-IDE complex structure PDB ID 3HGZ [47,48], according to a new set of criteria [33] as defined in the section of Materials and Methods.
  • a total of 39 (Table 6) interfacial side chain hydrogen bonds were structurally identified for the amylin-IDE complex structure PDB ID 2G48 [45,46], according to a new set of criteria [33] as defined in the section of Materials and Methods.
  • among the 39, 9 (Table 6) interfacial side chain hydrogen bonds were structurally identified at the binding interface of IDE and amylin for the amylin-IDE complex structure PDB ID 2G48 [45,46], according to a new set of criteria [33] as defined in the section of Materials and Methods.
  • a total of 15 (Table 7) interfacial side chain hydrogen bonds were structurally identified for the amylin-IDE complex structure PDB ID 3HGZ [47,48], according to a new set of criteria [33] as defined in the section of Materials and Methods.
  • among the 15, only four (Table 7) interfacial side chain hydrogen bonds were structurally identified at the binding interface of IDE and amylin for the amylin-IDE complex structure PDB ID 3HGZ [47,48], according to a new set of criteria [33] as defined in the section of Materials and Methods.

4.2. Structural identification of an electrostatic hotspot at amylin-IDE binding interface

Among the residue-specific electrostatic interactions at the amylin-IDE binding interface described above, one extraordinary pair of oppositely charged residues appear rather outstanding: lysine (Lys1, K1) residue of amylin and Glu341 (E341) of IDE, as this residue pair is the only one where interfacial electrostatic interactions were structurally identified at the amylin-IDE binding interface for two experimental structures representing the amylin-IDE complex, with PDB IDs: 2G48 [45,46] and 3HGZ [47,48] as listed in Table 1.
Take 2G48 [45,46] for example, one 3.514 Å interfacial salt bridge (Figurer̃efpymol2) was found to be formed between the oppositely charged side chains of Lys1 of amylin and Glu341 of IDE, while two interfacial salt bridges (2.441 and 3.179 Å) were also found to be formed between the oppositely charged side chains of Lys1 of amylin and Glu341 of IDE for 3HGZ [47,48]. Moreover, while no further salt bridges were found to be formed according to the old set of criteria as defined in [33], they are still quite close to each other for the side chains of Lys1 of amylin and Glu341 of IDE. Take 2G48 [45,46] for example, apart from the salt bridge, other positively charged side chain atoms of Lys1 of amylin are only 4.876 and 5.297 Å away from the negatively charged side chain oxygens of Glu341 of IDE, as shown in Figuresr̃efpymol2 and Figure 3.
In addition to interfacial salt bridges, the one extraordinary pair, i.e., Lys1 of amylin and Glu341 of IDE, were also found to be involved in a set of interfacial side chain hydrogen bonds, as shown by two yellow rows in Table 7 and also two yellow rows in Table 6, according to a new set of criteria [33] as defined in the section of Materials and Methods. Finally, what even more interesting is one interfacial side chain bridges formed between Lys1 of amylin and Glu341 of IDE, as shown in Figuresr̃efpymol2 and Figure 3, the main chain amide nitrogen (positively charged) of Lys1 of amylin is only 3.4 Å away from the negatively charged side chain oxygen of Glu341 of IDE, making the residue pair close to each other enough to form a strong main chain-side chain interfacial salt bridge, further strengthening the binding between amylin and IDE.
Taken together, these three sets of interfacial electrostatic interactions between Lys1 of amylin and Glu341 of IDE, i.e., side chain-side chain interfacial salt bridges, side chain-side chain interfacial hydrogen bonds, main chain-side chain interfacial salt bridges, highlights an extraordinary electrostatic hotspot at the amylin-IDE binding interface, making it an attractive precise target for small molecule inhibitor to reach inside IDE (the cage, Figurer̃efpymol1) and disrupt the amylin-IDE interaction for improved metabolic homeostasis.

5. Conclusion

Starting from two experimental structures representing the amylin-IDE complex, with PDB IDs: 2G48 [45,46] and 3HGZ [47,48] as listed in Table 1, this article puts forward a set of structural characterization for residue-specific electrostatic interactions at the amylin-IDE binding interface, as listed in Table 2, Table 3, Table 4, Table 5, Table 6 and Table 7. Moreover, this article also highlights one intriguing electrostatic hotspot (Figuresr̃efpymol2 and Figure 3) between the first N-terminal lysine (Lys1, K1) residue of amylin and Glu341 (E341) of IDE, with both interfacial salt bridges and side chain hydrogen bonds formed between the two oppositely charged residues sitting at the binding interface of amylin-IDE.
To sum up,
  • the structural identification of electrostatic hotspots at the binding interface of amylin and IDE presents a promising avenue for the development of small molecules capable of disrupting this crucial interaction [54,55,56].
  • This finding also contributes to the growing body of knowledge aimed at unraveling the intricacies of protein–protein interactions and provides a foundation for future research endeavors in the development of targeted therapeutics for metabolic disorders, particularly diabetes (T2DM) and obesity [57,58].
  • The rationale for targeting electrostatic hotspots in the amylin-IDE interaction lies in the role of such sites as preferred binding locations for drug-like small molecules. By pinpointing these hotspots, we aim to provide a precise target for the development of small molecules capable of disrupting the amylin-IDE interaction. The potential therapeutic implications of such disruptors extend to modulating glucose homeostasis and mitigating the risk of amyloid formation, which is particularly relevant in the context of type 2 diabetes.

6. Discussion

6.1. Disrupting the amylin-IDE interaction: a drug discovery and design perspective

In drug discovery and design, targeting the interaction between amylin and IDE could be a potential strategy for therapeutic intervention. As amylin is involved in the regulation of blood glucose levels, manipulating its interaction with IDE might be explored as a way to modulate glucose homeostasis. While this article identified an intriguing electrostatic hotspots at the amylin-IDE binding interface, offering precise targets for therapeutic intervention and the development of small molecule inhibitors targeting the amylin-IDE interaction, the inhibition of the interaction between amylin and IDE can also lead to side effects such as glucose intolerance [59], as the intricate interplay between amylin and IDE constitutes a pivotal aspect of glucose homeostasis, with implications for the prevention of amyloid formation and maintenance of metabolic health [60,61,62]. Moreover, disrupting the interaction between amylin and IDE could have unintended consequences, as IDE is involved in the degradation of various peptides, and altering its interaction with amylin might affect the levels of other important regulatory molecules, selectivity is a key challenge in the design of small molecule inhibitor or even other molecular modalities such as small peptide of peptide-small molecule conjugate. Finally, still essential is a thorough understanding of the biological consequences of disrupting the amylin-IDE interaction, while disrupting the interaction between amylin and IDE could be a potential avenue for drug development, especially in the context of diabetes, obesity or even neurodegenerative diseases.

6.2. High-throughput comprehensive structural biophysical analysis: a methological perspective

In 2017, a comprehensive structural biophysical (CSB) approach was for the first time used in the analysis of experimental complex structures deposited in PDB [31] to address this question: how do SMA-linked mutations of SMN1 lead to structural/functional deficiency of the SMA protein i.e., the survivor motor neuron protein [33]? Here, the same structural biophysical approach was used here for the analysis of experimental complex structures of amylin and IDE, allowing for the precise identification of electrostatic hotspots at the binding interface of amylin and insulin-degrading enzyme. This level of precision aids in targeting specific regions for the development of small molecules. Moreover, By exploring the structural details and biophysical characteristics of the interaction, this approach provides valuable insights into the molecular interactions between amylin and insulin-degrading enzyme. Understanding these interactions is crucial for rational design of effective small molecule disruptors with high specificity, i.e., without affecting other biological processes. This specificity is crucial for minimizing off-target effects and enhancing the safety profile of potential therapeutic agents.
In addition, the information obtained through this approach contributes to rational drug design by providing a solid foundation for the development of small molecules. The identified hotspots serve as rational targets for disrupting the interaction, potentially enhancing the success rate of drug development efforts. Furthermore, in light of the increasingly large size of the Protein Data Bank, this CSB approach technically is applicable for a exhaustive analysis of the entire PDB for high-throughput extraction of structural and biophysical features [63,64] and continued generation and accumulation of synthetic structural and biophysical data with reasonable accuracy to support the development of machine learning-models such as GIBAC [65]. With this respect, however, in original PDB-format data, the experimentally determined atomic coordinates are presented in the ATOM records, and chances are that they do not exactly match the sequence (consisting of nucleic and/or amino acid residues) of the experimental sample per se, be it protein, DNA, RNA or their complexes with drugs and/or other small molecules [66,67].
Take amylin and IDE for example, the fasta format sequence of amylin in PDB ID 2G48 [45,46] is as below:
>2G48_2|Chains C, D|Islet amyloid polypeptide|null [45,46]
KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY
while the fasta format sequence of amylin in PDB ID 3HGZ [47,48] is as below:
>3HGZ_2|Chains C[auth D], D[auth E]|Islet amyloid polypeptide|null (9606) [47,48]
KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY
As listed in Table 8, in PDB ID 2G48 [45,46], there are a total of 37 residues for amylin in the experimental sample, with atomic coordinate information of 19 missing for chain C (amylin in PDB ID 2G48) and 20 missing for chain D (amylin in PDB ID 2G48), while in PDB ID 3HGZ [47,48], there are also a total of 37 residues for amylin in the experimental sample, with atomic coordinate information of 30 missing for chain D (amylin in PDB ID 3HGZ) and 27 missing for chain D (amylin in PDB ID 3HGZ).
As previously described in [68] in 2017, the past 53 years of experimental structure deposition in PDB also saw continued accumulation of experimentally uncharted territories (EUTs) inside it, reaching a point already where it is increasingly pressing for biomolecular structures (especially membrane proteins like Ca2+ channel [69,70]) to be experimentally determined in an EUT-less manner, as exemplified here again by the experimentally uncharted territories (EUTs) in two structural models representing IDE-amylin complex (PDB IDs: 2G48 [45,46] and 3HGZ [47,48]).

7. Ethical statement

No ethical approval is required.

8. Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the author used OpenAI’s ChatGPT in order to improve the readability of the manuscript, and to make it as concise and short as possible. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.

Author Contributions

Conceptualization, W.L.; methodology, W.L.; software, W.L.; validation, W.L.; formal analysis, W.L.; investigation, W.L.; resources, W.L.; data duration, W.L.; writing–original draft preparation, W.L.; writing–review and editing, W.L.; visualization, W.L.; supervision, W.L.; project administration, W.L.; funding acquisition, not applicable.

Funding

This research received no external funding.

Conflicts of Interest

The author declares no conflict of interest.

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Figure 1. The overall structure of human insulin-degrading enzyme in complex with amylin. This figure is prepared by PyMol [53] with PDB ID 2G48 [45,46]. In this figure, IDE as an amylin-degrading enzyme is like a cage for amylin as its substrate, making it a preferable choice for the potential development of small molecule inhibitor(s) to reach inside IDE (the cage) and disrupt the amylin-IDE interaction for improved metabolic homeostasis.
Figure 1. The overall structure of human insulin-degrading enzyme in complex with amylin. This figure is prepared by PyMol [53] with PDB ID 2G48 [45,46]. In this figure, IDE as an amylin-degrading enzyme is like a cage for amylin as its substrate, making it a preferable choice for the potential development of small molecule inhibitor(s) to reach inside IDE (the cage) and disrupt the amylin-IDE interaction for improved metabolic homeostasis.
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Figure 2. Two sets of interfacial salt bridges (dotted yellow sticks) between Lys1 (K1) of amylin and Glu341 (E341) of IDE. This figure is prepared by PyMol [53] with PDB ID 2G48 [45,46]. In this figure, the color scheme is the same as in Figure 1.
Figure 2. Two sets of interfacial salt bridges (dotted yellow sticks) between Lys1 (K1) of amylin and Glu341 (E341) of IDE. This figure is prepared by PyMol [53] with PDB ID 2G48 [45,46]. In this figure, the color scheme is the same as in Figure 1.
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Figure 3. A closer (than Figurer̃efpymol2) view of two sets of interfacial salt bridges (dotted yellow sticks) between Lys1 (K1) of amylin and Glu341 (E341) of IDE. This figure is prepared by PyMol [53] with PDB ID 2G48 [45,46]. In this figure, the color scheme is the same as in Figure 1.
Figure 3. A closer (than Figurer̃efpymol2) view of two sets of interfacial salt bridges (dotted yellow sticks) between Lys1 (K1) of amylin and Glu341 (E341) of IDE. This figure is prepared by PyMol [53] with PDB ID 2G48 [45,46]. In this figure, the color scheme is the same as in Figure 1.
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Table 1. Experimentally determined amylin-related structures in the Protein Data Bank (PDB [31]) as of February 1, 2024. QUERY: Full Text = "amylin". In this table, the two structural models representing IDE-amylin complex are highlighted in two yellow rows, i.e., PDB IDs: 2G48 [45,46] and 3HGZ [47,48].
Table 1. Experimentally determined amylin-related structures in the Protein Data Bank (PDB [31]) as of February 1, 2024. QUERY: Full Text = "amylin". In this table, the two structural models representing IDE-amylin complex are highlighted in two yellow rows, i.e., PDB IDs: 2G48 [45,46] and 3HGZ [47,48].
PDB ID Structure Title
8AZ7 IAPP S20G plateau-phase fibril polymorph 4PF-LJ
8AZ6 IAPP S20G plateau-phase fibril polymorph 4PF-LU
8AZ5 IAPP S20G plateau-phase fibril polymorph 4PF-CU
8AZ4 IAPP S20G plateau-phase fibril polymorph 2PF-L
8AZ3 IAPP S20G growth-phase fibril polymorph 4PF-CU
8AZ2 IAPP S20G growth-phase fibril polymorph 3PF-CU
8AZ1 IAPP S20G growth-phase fibril polymorph 2PF-C
8AZ0 IAPP S20G growth-phase fibril polymorph 2PF-L
8AWT IAPP S20G lag-phase fibril polymorph 2PF-P
8T89 Racemic mixture of amyloid beta segment 16-KLVFFA-21 forms heterochiral rippled beta-sheet
8T86 Racemic mixture of amylin segment 25-AILSS-29 forms heterochiral rippled beta-sheet
8T84 Racemic mixture of amyloid beta segment 35-MVGGVV-40 forms heterochiral rippled beta-sheet, includes hexafluoroisopropanol
8T82 Racemic mixture of amyloid beta segment 35-MVGGVV-40 forms heterochiral rippled beta-sheet, includes pentafluoropropionic acid
8F2B Amylin 3 Receptor in complex with Gs and Pramlintide analogue peptide San45
8F2A Human Amylin3 Receptor in complex with Gs and Pramlintide analogue peptide San385 (Cluster 5 conformation)
8F0K Human Amylin3 Receptor in complex with Gs and Pramlintide analogue peptide San385
8F0J Calcitonin Receptor in complex with Gs and Pramlintide analogue peptide San45
7YKW Structure of hIAPP fibril at 3.6 Angstroms resolution
7YL7 Structure of hIAPP-TF-type3
7YL3 Structure of hIAPP-TF-type1
7YL0 Structure of hIAPP-TF-type2
8AX7 Crystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0031448
8AX6 Crystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0029882
8AX5 Crystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0029881
7P0I Crystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor Compound 13
7P0F Crystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0028125
7TYX Human Amylin2 Receptor in complex with Gs and rat amylin peptide
7TYN Calcitonin Receptor in complex with Gs and salmon calcitonin peptide
7TYI Calcitonin Receptor in complex with Gs and rat amylin peptide, CT-like state
7TZF Human Amylin3 Receptor in complex with Gs and rat amylin peptide
7TYY Human Amylin2 Receptor in complex with Gs and salmon calcitonin peptide
7TYW Human Amylin1 Receptor in complex with Gs and salmon calcitonin peptide
7TYO Calcitonin receptor in complex with Gs and human calcitonin peptide
7TYL Calcitonin Receptor in complex with Gs and rat amylin peptide, bypass motif
7TYH Human Amylin2 Receptor in complex with Gs and human calcitonin peptide
7TYF Human Amylin1 Receptor in complex with Gs and rat amylin peptide
7VV0 Cryo-EM structure of pseudoallergen receptor MRGPRX2 complex with PAMP-12, local
7M65 Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils seeded by patient extracted fibrils, polymorph 4
7M64 Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils seeded by patient extracted fibrils, polymorph 3
7M62 Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils seeded by patient extracted fibrils, polymorph 2
7M61 Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils seeded by patient extracted fibrils, polymorph 1
7BG0 Fusion of MBP and the backbone of the long-acting amylin analog AM833.
7KNU CryoEM structure of the CGRP receptor with bound CGRP peptide in a detergent micelle
7KNT CryoEM structure of the apo-CGRP receptor in a detergent micelle
6ZRR three-protofilament amyloid structure of S20G variant of human amylin (IAPP - Islet Amyloid Polypeptide)
6ZRQ two-protofilament amyloid structure of S20G variant of human amylin (IAPP - islet amyloid polypeptide)
6ZRF amyloid structure of amylin (IAPP - islet amyloid polypeptide)
6V2E Crystal structure of the human CLR:RAMP2 extracellular domain heterodimer with bound high-affinity adrenomedullin S45R/K46L/S48G/Q50W variant
6ZIS Crystal structure of a CGRP receptor ectodomain heterodimer with bound high affinity inhibitor
6ZHO Crystal structure of a CGRP receptor ectodomain heterodimer with bound high affinity inhibitor
6VW2 Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils
6UVA CryoEM Structure of the active Adrenomedullin 2 receptor G protein complex with adrenomedullin 2 peptide
6UUS CryoEM Structure of the active Adrenomedullin 2 receptor G protein complex with adrenomedullin peptide
6UUN CryoEM Structure of the active Adrenomedullin 1 receptor G protein complex with adrenomedullin peptide
6Y1A Amyloid fibril structure of islet amyloid polypeptide
6UCK proIAPP in DPC Micelles - Two-Conformer Ensemble Refinement, Bent Conformer
6UCJ proIAPP in DPC Micelles - Two-Conformer Ensemble Refinement, Open Conformer
6UMG Crystal structure of erenumab Fab bound to the extracellular domain of CGRP receptor
6PGQ Crystal structure of N-glycosylated human calcitonin receptor extracellular domain in complex with salmon calcitonin (22-32)
6PFO Crystal structure of N-glycosylated human calcitonin receptor extracellular domain in complex with salmon calcitonin (16-32)
6NIY A high-resolution cryo-electron microscopy structure of a calcitonin receptor-heterotrimeric Gs protein complex
6E3Y Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor
6D1U Crystal structure of the human CLR:RAMP1 extracellular domain heterodimer in complex with adrenomedullin 2/intermedin
5V6Y Crystal structure of the human CLR:RAMP1 extracellular domain heterodimer with bound high-affinity and altered selectivity adrenomedullin variant
5UZ7 Volta phase plate cryo-electron microscopy structure of a calcitonin receptor-heterotrimeric Gs protein complex
5MGQ Solution structure of oxidized and amidated human IAPP (1-37), the diabetes II peptide.
5KO0 Human Islet Amyloid Polypeptide Segment 15-FLVHSSNNFGA-25 Determined by MicroED
5KNZ Human Islet Amyloid Polypeptide Segment 19-SGNNFGAILSS-29 with Early Onset S20G Mutation Determined by MicroED
5K5G Structure of human islet amyloid polypeptide in complex with an engineered binding protein
5II0 Crystal structure of the human calcitonin receptor ectodomain in complex with a truncated salmon calcitonin analogue
4RWG Crystal structure of the CLR:RAMP1 extracellular domain heterodimer with bound high affinity CGRP analog
4RWF Crystal structure of the CLR:RAMP2 extracellular domain heterodimer with bound adrenomedullin
3AQE Crystal structure of the extracellular domain of human RAMP2
3AQF Crystal structure of the human CRLR/RAMP2 extracellular complex
2L7S Determination of the three-dimensional structure of adrenomedullin, a first step towards the analysis of its interactions with receptors and small molecules
2L86 Solution NMR structure of human amylin in SDS micelles at pH 7.3
2XVT Structure of the extracellular domain of human RAMP2
3N7S Crystal structure of the ectodomain complex of the CGRP receptor, a Class-B GPCR, reveals the site of drug antagonism
3N7R Crystal structure of the ectodomain complex of the CGRP receptor, a Class-B GPCR, reveals the site of drug antagonism
3N7P Crystal structure of the ectodomain complex of the CGRP receptor, a Class-B GPCR, reveals the site of drug antagonism
3HGZ Crystal structure of human insulin-degrading enzyme in complex with amylin
2WK3 Crystal structure of human insulin-degrading enzyme in complex with amyloid-beta (1-42)
2KIB Protein Fibril
3E50 Crystal structure of human insulin degrading enzyme in complex with transforming growth factor-alpha
3E4Z Crystal structure of human insulin degrading enzyme in complex with insulin-like growth factor II
3FTR Structure of an amyloid forming peptide SSTNVG from IAPP (alternate polymorph)
3FTL NVGSNTY segment from Islet Amyloid Polypeptide (IAPP or Amylin), dehydrated crystal form
3FTK NVGSNTY segment from Islet Amyloid Polypeptide (IAPP or Amylin), hydrated crystal form
3FTH NFLVHSS segment from Islet Amyloid Polypeptide (IAPP or Amylin)
3FR1 NFLVHS segment from Islet Amyloid Polypeptide (IAPP or Amylin)
3FPO HSSNNF segment from Islet Amyloid Polypeptide (IAPP or Amylin)
3G7W Islet Amyloid Polypeptide (IAPP or Amylin) Residues 1 to 22 fused to Maltose Binding Protein
3G7V Islet Amyloid Polypeptide (IAPP or Amylin) fused to Maltose Binding Protein
2KJ7 Three-Dimensional NMR Structure of Rat Islet Amyloid Polypeptide in DPC micelles
2KB8 The dynamic alpha-helix structure of micelle-bound human amylin.
3DGJ NNFGAIL segment from Islet Amyloid Polypeptide (IAPP or amylin)
3DG1 Segment SSTNVG derived from IAPP
2YX8 Crystal structure of the extracellular domain of human RAMP1
2G48 crystal structure of human insulin-degrading enzyme in complex with amylin
2FLY Proadrenomedullin N-Terminal 20 Peptide
1KUW High-Resolution Structure and Localization of Amylin Nucleation Site in Detergent Micelle
Table 2. Interfacial salt bridging network analysis of the two structural models of IDE-amylin complex (Table 1), i.e., PDB IDs 2G48 [45,46] and 3HGZ [47,48] according to the old set of criteria as in [33]. In this table, the residue naming scheme is Chain ID_residue name_residue number. As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
Table 2. Interfacial salt bridging network analysis of the two structural models of IDE-amylin complex (Table 1), i.e., PDB IDs 2G48 [45,46] and 3HGZ [47,48] according to the old set of criteria as in [33]. In this table, the residue naming scheme is Chain ID_residue name_residue number. As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
PDB ID Residue A Atom A Residue B Atom B Distance (Å)
2G48 A_ARG_722 NH1 B_ASP_706 OD1 2.987
2G48 A_ARG_722 NH1 B_ASP_706 OD2 2.560
2G48 A_ARG_722 NH2 B_GLU_702 OE2 3.255
2G48 A_LYS_756 NZ B_ASP_706 OD1 3.852
2G48 B_ARG_722 NH1 A_ASP_706 OD1 2.728
2G48 B_ARG_722 NH1 A_ASP_706 OD2 3.524
2G48 B_ARG_722 NH2 A_ASP_706 OD1 3.653
2G48 B_LYS_756 NZ A_ASP_706 OD1 3.253
2G48 B_LYS_756 NZ A_ASP_706 OD2 2.575
2G48 C_LYS_1 NZ A_GLU_341 OE1 3.514
3HGZ A_ARG_164 NH1 B_GLU_408 OE1 3.083
3HGZ A_ARG_164 NH1 B_GLU_408 OE2 3.662
3HGZ A_ARG_164 NH2 B_GLU_408 OE1 3.032
3HGZ B_LYS_327 NZ A_GLU_880 OE1 3.476
3HGZ D_LYS_1 NZ A_GLU_341 OE1 2.441
3HGZ E_LYS_1 NZ B_GLU_341 OE1 3.179
Table 3. 2G48-specific interfacial side chain and main chain hydrogen bonding analysis according to the old set of criteria as in [33]. In this table, the residue naming scheme is Chain ID_residue name_residue number, A D H represents the angle formed by acceptor (A), donor (D) and hydrogen (H) ( A D H ) . As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
Table 3. 2G48-specific interfacial side chain and main chain hydrogen bonding analysis according to the old set of criteria as in [33]. In this table, the residue naming scheme is Chain ID_residue name_residue number, A D H represents the angle formed by acceptor (A), donor (D) and hydrogen (H) ( A D H ) . As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
PDB ID Acceptor (A) Donor (D) Hydrogen (H) D-A (Å)   H-A (Å)   ADH ( )
2G48 O, C_LYS_1 N, A_GLY_361 H, A_GLY_361 2.72 1.72 5.66
2G48 OE2, B_GLU_699 OG, A_SER_761 HG, A_SER_761 2.52 1.67 22.41
2G48 O, C_LEU_16 NH2, A_ARG_824 HH21, A_ARG_824 2.98 2.09 22.98
2G48 O, D_ASN_14 N, B_THR_142 H, B_THR_142 2.89 1.99 21.69
2G48 O, D_LYS_1 N, B_GLY_361 H, B_GLY_361 2.89 1.89 5.77
2G48 OD1, A_ASP_706 NH1, B_ARG_722 HH12, B_ARG_722 2.73 1.91 29.32
2G48 OD2, A_ASP_706 NZ, B_LYS_756 HZ1, B_LYS_756 2.57 1.59 10.38
2G48 OE2, A_GLU_699 OG, B_SER_761 HG, B_SER_761 2.51 1.64 19.94
2G48 O, A_GLY_361 N, C_ASN_3 H, C_ASN_3 2.65 1.76 22.83
2G48 O, A_ALA_140 N, C_LEU_16 H, C_LEU_16 2.97 2.01 15.18
2G48 OE1, B_GLU_341 N, D_LYS_1 H2, D_LYS_1 2.85 1.85 6.72
2G48 O, B_GLY_361 N, D_ASN_3 H, D_ASN_3 2.67 1.76 20.40
2G48 O, B_GLN_363 ND2, D_ASN_3 HD22, D_ASN_3 2.73 1.89 26.92
2G48 O, B_ALA_140 N, D_LEU_16 H, D_LEU_16 2.83 1.95 23.79
Table 4. 2G48-specific interfacial side chain hydrogen bonding analysis according to the old set of criteria as in [33]. In this table, the residue naming scheme is Chain ID_residue name_residue number, A D H represents the angle formed by acceptor (A), donor (D) and hydrogen (H) ( A D H ) . As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
Table 4. 2G48-specific interfacial side chain hydrogen bonding analysis according to the old set of criteria as in [33]. In this table, the residue naming scheme is Chain ID_residue name_residue number, A D H represents the angle formed by acceptor (A), donor (D) and hydrogen (H) ( A D H ) . As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
PDB ID Acceptor (A) Donor (D) Hydrogen (H) D-A (Å)   H-A (Å)   ADH ( )
2G48 OE2, B_GLU_699 OG, A_SER_761 HG, A_SER_761 2.52 1.67 22.41
2G48 OD1, A_ASP_706 NH1, B_ARG_722 HH12, B_ARG_722 2.73 1.91 29.32
2G48 OD2, A_ASP_706 NZ, B_LYS_756 HZ1, B_LYS_756 2.57 1.59 10.38
2G48 OE2, A_GLU_699 OG, B_SER_761 HG, B_SER_761 2.51 1.64 19.94
Table 5. Interfacial salt bridging network analysis within the PDB entries (2G48 [45,46] and 3HGZ [47,48]) according to a new set of criteria [33] as defined in the section of Materials and Methods. In this table, the residue naming scheme is Chain ID_residue name_residue number. As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
Table 5. Interfacial salt bridging network analysis within the PDB entries (2G48 [45,46] and 3HGZ [47,48]) according to a new set of criteria [33] as defined in the section of Materials and Methods. In this table, the residue naming scheme is Chain ID_residue name_residue number. As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
PDB ID Residue A Atom A Residue B Atom B Distance (Å)
2G48 A_ARG_722 NH1 B_GLU_702 OE2 4.700
2G48 A_ARG_722 NH1 B_ASP_706 OD1 2.987
2G48 A_ARG_722 NH1 B_ASP_706 OD2 2.560
2G48 A_ARG_722 NH2 B_GLU_702 OE1 5.134
2G48 A_ARG_722 NH2 B_GLU_702 OE2 3.255
2G48 A_ARG_722 NH2 B_ASP_706 OD1 4.711
2G48 A_ARG_722 NH2 B_ASP_706 OD2 4.433
2G48 A_LYS_756 NZ B_GLU_702 OE2 5.525
2G48 A_LYS_756 NZ B_ASP_706 OD1 3.852
2G48 A_LYS_756 NZ B_ASP_706 OD2 5.449
2G48 A_LYS_1009 NZ B_GLU_990 OE1 5.840
2G48 B_ARG_722 NH1 A_ASP_706 OD1 2.728
2G48 B_ARG_722 NH1 A_ASP_706 OD2 3.524
2G48 B_ARG_722 NH2 A_GLU_702 OE1 5.354
2G48 B_ARG_722 NH2 A_ASP_706 OD1 3.653
2G48 B_ARG_722 NH2 A_ASP_706 OD2 5.078
2G48 B_LYS_756 NZ A_ASP_706 OD1 3.253
2G48 B_LYS_756 NZ A_ASP_706 OD2 2.575
2G48 B_LYS_1009 NZ A_GLU_997 OE1 5.095
2G48 C_LYS_1 NZ A_GLU_341 OE1 3.514
2G48 C_LYS_1 NZ A_GLU_341 OE2 4.876
2G48 C_LYS_1 NZ A_GLU_612 OE2 5.297
3HGZ A_LYS_123 NZ B_ASP_416 OD1 4.754
3HGZ A_ARG_164 NH1 B_GLU_408 OE1 3.083
3HGZ A_ARG_164 NH1 B_GLU_408 OE2 3.662
3HGZ A_ARG_164 NH2 B_GLU_408 OE1 3.032
3HGZ A_ARG_164 NH2 B_GLU_408 OE2 4.613
3HGZ A_LYS_884 NZ B_GLU_457 OE1 4.680
3HGZ B_HIS_53 ND1 A_GLU_875 OE1 4.690
3HGZ B_HIS_53 NE2 A_GLU_875 OE1 4.274
3HGZ B_LYS_327 NZ A_GLU_880 OE1 3.476
3HGZ B_LYS_327 NZ A_GLU_880 OE2 5.083
3HGZ B_LYS_415 NZ A_GLU_133 OE1 5.186
3HGZ D_LYS_1 NZ A_GLU_341 OE1 2.441
3HGZ D_LYS_1 NZ A_GLU_341 OE2 4.468
3HGZ E_LYS_1 NZ B_GLU_341 OE1 3.179
3HGZ E_LYS_1 NZ B_GLU_341 OE2 5.147
Table 6. 2G48 [45,46]-specific interfacial side chain hydrogen bonding analysis according to a new set of criteria [33] as defined in the section of Materials and Methods. In this table, the residue naming scheme is Chain ID_residue name_residue number, A D H represents the angle formed by acceptor (A), donor (D) and hydrogen (H) ( A D H ) . As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
Table 6. 2G48 [45,46]-specific interfacial side chain hydrogen bonding analysis according to a new set of criteria [33] as defined in the section of Materials and Methods. In this table, the residue naming scheme is Chain ID_residue name_residue number, A D H represents the angle formed by acceptor (A), donor (D) and hydrogen (H) ( A D H ) . As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
PDB ID Acceptor (A) Donor (D) Hydrogen (H) D-A (Å)   H-A (Å)   ADH ( )
2G48 NE2, C_HIS_18 NZ, A_LYS_192 HZ3, A_LYS_192 4.89 4.23 44.36
2G48 OD1, C_ASN_14 OG1, A_THR_220 HG1, A_THR_220 3.22 2.28 9.48
2G48 ND2, C_ASN_14 OG1, A_THR_220 HG1, A_THR_220 3.21 2.65 47.15
2G48 OE1, B_GLN_718 NE2, A_HIS_589 HE2, A_HIS_589 4.14 3.18 16.40
2G48 NE2, B_GLN_718 NE2, A_HIS_589 HE2, A_HIS_589 4.55 3.58 13.52
2G48 OG, B_SER_721 NH1, A_ARG_711 HH12, A_ARG_711 4.90 3.97 20.43
2G48 NE2, B_GLN_718 NH2, A_ARG_711 HH21, A_ARG_711 3.92 3.14 33.89
2G48 OG, B_SER_721 NH2, A_ARG_711 HH21, A_ARG_711 4.86 3.92 19.33
2G48 NE2, B_HIS_589 NE2, A_GLN_718 HE22, A_GLN_718 3.40 2.61 32.75
2G48 OD1, B_ASP_706 NH1, A_ARG_722 HH12, A_ARG_722 2.99 2.41 46.66
2G48 OE2, B_GLU_702 NH2, A_ARG_722 HH22, A_ARG_722 3.25 2.43 29.82
2G48 OE1, B_GLU_699 OG, A_SER_761 HG, A_SER_761 3.84 2.92 13.96
2G48 OE2, B_GLU_699 OG, A_SER_761 HG, A_SER_761 2.52 1.67 22.41
2G48 OD2, B_ASP_586 NE2, A_GLN_762 HE22, A_GLN_762 3.64 3.02 45.51
2G48 NE2, B_GLN_770 NE2, A_GLN_770 HE21, A_GLN_770 4.30 3.39 22.59
2G48 OG, D_SER_19 ND2, B_ASN_139 HD22, B_ASN_139 4.49 3.91 48.99
2G48 OD1, D_ASN_14 OG1, B_THR_220 HG1, B_THR_220 3.09 2.14 8.07
2G48 ND2, D_ASN_14 OG1, B_THR_220 HG1, B_THR_220 3.42 2.85 46.81
2G48 OE1, A_GLN_718 NE, B_ARG_711 HE, B_ARG_711 4.89 3.96 20.15
2G48 OG, A_SER_721 NE, B_ARG_711 HE, B_ARG_711 4.94 4.15 34.49
2G48 OG, A_SER_721 NH1, B_ARG_711 HH12, B_ARG_711 4.28 3.36 20.95
2G48 OD1, A_ASP_706 NH1, B_ARG_722 HH12, B_ARG_722 2.73 1.91 29.32
2G48 OD2, A_ASP_706 NH1, B_ARG_722 HH12, B_ARG_722 3.52 2.69 29.77
2G48 OD1, A_ASP_706 NH2, B_ARG_722 HH21, B_ARG_722 3.65 3.09 49.48
2G48 OD2, A_ASP_706 NZ, B_LYS_756 HZ1, B_LYS_756 2.57 1.59 10.38
2G48 OE1, A_GLU_699 OG, B_SER_761 HG, B_SER_761 4.00 3.07 11.68
2G48 OE2, A_GLU_699 OG, B_SER_761 HG, B_SER_761 2.51 1.64 19.94
2G48 OD2, A_ASP_586 NE2, B_GLN_762 HE22, B_GLN_762 4.17 3.60 49.58
2G48 NE2, A_GLN_770 NE2, B_GLN_770 HE21, B_GLN_770 4.30 3.46 30.40
2G48 OD1, D_ASN_22 NH2, B_ARG_847 HH22, B_ARG_847 4.10 3.14 17.00
2G48 ND2, D_ASN_22 NH2, B_ARG_847 HH22, B_ARG_847 4.95 3.97 13.60
2G48 OE1, A_GLU_341 NZ, C_LYS_1 HZ3, C_LYS_1 3.51 2.72 32.95
2G48 OE2, A_GLU_341 NZ, C_LYS_1 HZ3, C_LYS_1 4.88 4.20 43.27
2G48 ND1, A_HIS_332 OG1, C_THR_4 HG1, C_THR_4 3.10 2.41 37.40
2G48 OG1, A_THR_220 ND2, C_ASN_14 HD22, C_ASN_14 3.21 2.37 28.58
2G48 NE2, A_HIS_679 NE2, C_HIS_18 HE2, C_HIS_18 4.27 3.60 43.28
2G48 OG1, B_THR_220 ND2, D_ASN_14 HD22, D_ASN_14 3.42 2.67 36.00
2G48 NE2, B_HIS_679 NE2, D_HIS_18 HE2, D_HIS_18 4.32 3.75 49.86
Table 7. 3HGZ [47,48]-specific interfacial side chain hydrogen bonding analysis according to a new set of criteria [33] as defined in the section of Materials and Methods. In this table, the residue naming scheme is Chain ID_residue name_residue number, A D H represents the angle formed by acceptor (A), donor (D) and hydrogen (H) ( A D H ) . As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
Table 7. 3HGZ [47,48]-specific interfacial side chain hydrogen bonding analysis according to a new set of criteria [33] as defined in the section of Materials and Methods. In this table, the residue naming scheme is Chain ID_residue name_residue number, A D H represents the angle formed by acceptor (A), donor (D) and hydrogen (H) ( A D H ) . As defined in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48], chains A and B represent IDE in 3HGZ, chains D and E represent amylin in 3HGZ, while chains A and B represent IDE in 2G48, and chains C and D represent amylin in 2G48, respectively.
PDB ID Acceptor (A) Donor (D) Hydrogen (H) D-A (Å)   H-A (Å)   ADH ( )
3HGZ NE2, B_GLN_407 NZ, A_LYS_120 HZ3, A_LYS_120 4.83 4.00 31.04
3HGZ OE1, B_GLU_408 NH1, A_ARG_164 HH11, A_ARG_164 3.08 2.20 24.18
3HGZ OE2, B_GLU_408 NH1, A_ARG_164 HH11, A_ARG_164 3.66 2.70 14.52
3HGZ OE1, B_GLU_408 NH2, A_ARG_164 HH21, A_ARG_164 3.03 2.13 21.99
3HGZ OE2, B_GLU_408 NH2, A_ARG_164 HH21, A_ARG_164 4.61 3.89 39.58
3HGZ OE1, B_GLN_412 NH2, A_ARG_164 HH22, A_ARG_164 3.72 2.94 34.36
3HGZ OE1, B_GLU_457 OG1, A_THR_878 HG1, A_THR_878 2.79 2.15 40.71
3HGZ OE2, B_GLU_457 OG1, A_THR_878 HG1, A_THR_878 3.07 2.47 43.72
3HGZ OE1, B_GLU_457 NZ, A_LYS_884 HZ3, A_LYS_884 4.68 3.74 18.88
3HGZ OG1, B_THR_55 NZ, A_LYS_933 HZ2, A_LYS_933 3.39 2.77 44.49
3HGZ OE1, A_GLU_880 NZ, B_LYS_327 HZ1, B_LYS_327 3.48 2.53 17.30
3HGZ OE1, A_GLU_341 NZ, D_LYS_1 HZ1, D_LYS_1 2.44 1.85 44.11
3HGZ OH, A_TYR_609 NZ, D_LYS_1 HZ2, D_LYS_1 3.91 3.25 43.14
3HGZ OE1, B_GLU_341 NZ, E_LYS_1 HZ2, E_LYS_1 3.18 2.42 34.86
3HGZ OH, B_TYR_609 NZ, E_LYS_1 HZ3, E_LYS_1 3.97 3.23 37.37
Table 8. Experimentally uncharted territories (EUTs) in two structural models representing IDE-amylin complex, as described by REMARK 465 in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48].
Table 8. Experimentally uncharted territories (EUTs) in two structural models representing IDE-amylin complex, as described by REMARK 465 in the PDB format content of PDB IDs: 2G48 [45,46] and 3HGZ [47,48].
PDB ID REMARK REMARK ID ResName Chain ID ResID
3HGZ REMARK 465 ASN D 3
3HGZ REMARK 465 THR D 4
3HGZ REMARK 465 ALA D 5
3HGZ REMARK 465 THR D 6
3HGZ REMARK 465 CYS D 7
3HGZ REMARK 465 ALA D 8
3HGZ REMARK 465 THR D 9
3HGZ REMARK 465 GLN D 10
3HGZ REMARK 465 ARG D 11
3HGZ REMARK 465 VAL D 17
3HGZ REMARK 465 HIS D 18
3HGZ REMARK 465 SER D 19
3HGZ REMARK 465 SER D 20
3HGZ REMARK 465 ASN D 21
3HGZ REMARK 465 ASN D 22
3HGZ REMARK 465 PHE D 23
3HGZ REMARK 465 GLY D 24
3HGZ REMARK 465 ALA D 25
3HGZ REMARK 465 ILE D 26
3HGZ REMARK 465 LEU D 27
3HGZ REMARK 465 SER D 28
3HGZ REMARK 465 SER D 29
3HGZ REMARK 465 THR D 30
3HGZ REMARK 465 ASN D 31
3HGZ REMARK 465 VAL D 32
3HGZ REMARK 465 GLY D 33
3HGZ REMARK 465 SER D 34
3HGZ REMARK 465 ASN D 35
3HGZ REMARK 465 THR D 36
3HGZ REMARK 465 TYR D 37
3HGZ REMARK 465 THR E 4
3HGZ REMARK 465 ALA E 5
3HGZ REMARK 465 THR E 6
3HGZ REMARK 465 THR E 9
3HGZ REMARK 465 GLN E 10
3HGZ REMARK 465 ARG E 11
3HGZ REMARK 465 VAL E 17
3HGZ REMARK 465 HIS E 18
3HGZ REMARK 465 SER E 19
3HGZ REMARK 465 SER E 20
3HGZ REMARK 465 ASN E 21
3HGZ REMARK 465 ASN E 22
3HGZ REMARK 465 PHE E 23
3HGZ REMARK 465 GLY E 24
3HGZ REMARK 465 ALA E 25
3HGZ REMARK 465 ILE E 26
3HGZ REMARK 465 LEU E 27
3HGZ REMARK 465 SER E 28
3HGZ REMARK 465 SER E 29
3HGZ REMARK 465 THR E 30
3HGZ REMARK 465 ASN E 31
3HGZ REMARK 465 VAL E 32
3HGZ REMARK 465 GLY E 33
3HGZ REMARK 465 SER E 34
3HGZ REMARK 465 ASN E 35
3HGZ REMARK 465 THR E 36
3HGZ REMARK 465 TYR E 37
2G48 REMARK 465 CYS C 7
2G48 REMARK 465 ALA C 8
2G48 REMARK 465 THR C 9
2G48 REMARK 465 ASN C 22
2G48 REMARK 465 PHE C 23
2G48 REMARK 465 GLY C 24
2G48 REMARK 465 ALA C 25
2G48 REMARK 465 ILE C 26
2G48 REMARK 465 LEU C 27
2G48 REMARK 465 SER C 28
2G48 REMARK 465 SER C 29
2G48 REMARK 465 THR C 30
2G48 REMARK 465 ASN C 31
2G48 REMARK 465 VAL C 32
2G48 REMARK 465 GLY C 33
2G48 REMARK 465 SER C 34
2G48 REMARK 465 ASN C 35
2G48 REMARK 465 THR C 36
2G48 REMARK 465 TYR C 37
2G48 REMARK 465 ALA D 5
2G48 REMARK 465 THR D 6
2G48 REMARK 465 CYS D 7
2G48 REMARK 465 ALA D 8
2G48 REMARK 465 THR D 9
2G48 REMARK 465 GLN D 10
2G48 REMARK 465 GLY D 24
2G48 REMARK 465 ALA D 25
2G48 REMARK 465 ILE D 26
2G48 REMARK 465 LEU D 27
2G48 REMARK 465 SER D 28
2G48 REMARK 465 SER D 29
2G48 REMARK 465 THR D 30
2G48 REMARK 465 ASN D 31
2G48 REMARK 465 VAL D 32
2G48 REMARK 465 GLY D 33
2G48 REMARK 465 SER D 34
2G48 REMARK 465 ASN D 35
2G48 REMARK 465 THR D 36
2G48 REMARK 465 TYR D 37
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