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The Structural Binding Mode of the Four Autotaxin Inhibitor Types that Differentially Affect Catalytic and Non-Catalytic Functions

Oncode Institute and Division of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Cancers 2019, 11(10), 1577; https://doi.org/10.3390/cancers11101577
Received: 10 September 2019 / Revised: 27 September 2019 / Accepted: 8 October 2019 / Published: 16 October 2019
(This article belongs to the Special Issue Lysophosphatidic Acid Signalling in Cancer)
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 it is implicated in many physiological processes and pathologies. ATX, therefore, has 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. In this review, first, we revisit what is known about ATX-mediated catalysis, crucially in light of allosteric regulation. Then, we present the known ATX catalysis-independent functions, including binding to cell surface integrins and proteoglycans. Next, we analyse all crystal structures of ATX bound to inhibitors and present them based on the four inhibitor types that are established based on the binding to the orthosteric and/or the allosteric site. Finally, in light of these data we discuss how mechanistic differences might differentially modulate the activity of the ATX-LPA signalling axis, and clinical applications including cancer. View Full-Text
Keywords: lysophosphatidic acid; autotaxin; inhibitor; allosteric; orthosteric; lipid chaperone; signalling; GPCR lysophosphatidic acid; autotaxin; inhibitor; allosteric; orthosteric; lipid chaperone; signalling; GPCR
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Salgado-Polo, F.; Perrakis, A. The Structural Binding Mode of the Four Autotaxin Inhibitor Types that Differentially Affect Catalytic and Non-Catalytic Functions. Cancers 2019, 11, 1577.

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