Preprint Review Version 1 This version is not peer-reviewed

The potential of different Autotaxin inhibitor types regulating catalysis-dependent and -independent signalling

Version 1 : Received: 10 September 2019 / Approved: 11 September 2019 / Online: 11 September 2019 (13:18:21 CEST)

How to cite: Salgado Polo, F.; Perrakis, A. The potential of different Autotaxin inhibitor types regulating catalysis-dependent and -independent signalling. Preprints 2019, 2019090120 (doi: 10.20944/preprints201909.0120.v1). Salgado Polo, F.; Perrakis, A. The potential of different Autotaxin inhibitor types regulating catalysis-dependent and -independent signalling. Preprints 2019, 2019090120 (doi: 10.20944/preprints201909.0120.v1).

Abstract

Autotaxin (ATX) is a secreted lysophospholipase D, catalysing the conversion of lysophosphatidylcholine (LPC) to bioactive lysophosphatidic acid (LPA). LPA acts through two families of G protein-coupled receptors (GPCRs) controlling key cellular responses, and is implicated in many physiological processes and pathologies. ATX has therefore been established as an important drug target in the pharmaceutical industry. Structural and biochemical studies of ATX have shown that it has a bimetallic nucleophilic catalytic site, a substrate-binding (orthosteric) hydrophobic pocket that accommodates the lipid alkyl chain, and an allosteric tunnel that can accommodate various steroids and LPA. Here we first review what is known about ATX-mediated catalysis, crucially in light of allosteric regulation. We then present the known ATX catalysis-independent functions, including binding to cell-surface integrins and proteoglycans. In light of these data we then discuss the four types of ATX inhibitors, as classified depending on their binding to the orthosteric and/or the allosteric site. Finally, we analyse the binding mode of known members of all four types and discuss how mechanistic differences might differentially modulate the activity of the ATX-LPA signalling axis, and clinical applications including cancer.

Subject Areas

Lysophosphatidic acid; Autotaxin; inhibitor; allosteric; orthosteric; lipid chaperone; signalling, GPCR

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.