Porfetye, A.T.; Stege, P.; Rebollido-Rios, R.; Hoffmann, D.; Schrader, T.; Vetter, I.R. How Do Molecular Tweezers Bind to Proteins? Lessons from X-ray Crystallography. Molecules2024, 29, 1764.
Porfetye, A.T.; Stege, P.; Rebollido-Rios, R.; Hoffmann, D.; Schrader, T.; Vetter, I.R. How Do Molecular Tweezers Bind to Proteins? Lessons from X-ray Crystallography. Molecules 2024, 29, 1764.
Porfetye, A.T.; Stege, P.; Rebollido-Rios, R.; Hoffmann, D.; Schrader, T.; Vetter, I.R. How Do Molecular Tweezers Bind to Proteins? Lessons from X-ray Crystallography. Molecules2024, 29, 1764.
Porfetye, A.T.; Stege, P.; Rebollido-Rios, R.; Hoffmann, D.; Schrader, T.; Vetter, I.R. How Do Molecular Tweezers Bind to Proteins? Lessons from X-ray Crystallography. Molecules 2024, 29, 1764.
Abstract
To understand the biological relevance and mode of action of artificial protein ligands, crystal structures with their protein targets are essential. Here, we describe and investigate all known crystal structures that contain a so-called “molecular tweezer” or one of its derivatives with an attached natural ligand on the respective target protein. The aromatic ring system of these compounds is able to include lysine and arginine side chains, supported by one or two phosphate groups that are attached to the half-moon shaped molecule. We analyse the corresponding crystal structures with 14-3-3 proteins in complex with mono- and diphosphate tweezers. Furthermore, we solved crystal structures of two different tweezer variants in complex with the enzyme 1-Pyrroline-5-carboxyl-dehydrogenase (P5CDH), and found that the tweezers are bound to a lysine and methionine side chain, respectively. The different binding modes and their implications for affinity and specificity are discussed, as well as the general problems in crystallizing protein complexes with artificial ligands.
Keywords
protein crystallography; molecular tweezers; supramolecular chemistry; 14-3-3 proteins; P5CDH Pyrroline-5-carboxyl-dehydrogenase
Subject
Biology and Life Sciences, Life Sciences
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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