7Z3K

Autotaxin in complex with orthosteric site-binder CpdA

これはPDB形式変換不可エントリーです。

7Z3K の概要

• エントリーDOI: 10.2210/pdb7z3k/pdb
• 分子名称: Isoform 2 of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, GLYCEROL, [(2~{S},4~{R})-4-[2-[(3,5-dimethylphenyl)amino]-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-2-methyl-piperidin-1-yl]-(6-fluoranyl-1~{H}-benzotriazol-5-yl)methanone, ... (12 entities in total)
• 機能のキーワード: enpp2, lysophosphatidic acid, lipid chaperone, ; pulmonary fibrosis, gpcr, drug development, small-molecule inhibitor, hydrolase
• 由来する生物種: Rattus norvegicus (Norway rat)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 97649.49

構造登録者

Salgado-Polo, F.,Ford, P.,Heckmann, B.,Perrakis, A. (登録日: 2022-03-02, 公開日: 2023-01-25, 最終更新日: 2024-11-13)

主引用文献

Salgado-Polo, F.,Borza, R.,Matsoukas, M.T.,Marsais, F.,Jagerschmidt, C.,Waeckel, L.,Moolenaar, W.H.,Ford, P.,Heckmann, B.,Perrakis, A.
Autotaxin facilitates selective LPA receptor signaling.
Cell Chem Biol, 30:69-84.e14, 2023

PubMed Abstract: Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA) and P2Y (LPA) G protein-coupled receptors. ATX/LPA promotes several (patho)physiological processes, including in pulmonary fibrosis, thus serving as an attractive drug target. However, it remains unclear if clinical outcome depends on how different types of ATX inhibitors modulate the ATX/LPA signaling axis. Here, we show that the ATX "tunnel" is crucial for conferring key aspects of ATX/LPA signaling and dictates cellular responses independent of ATX catalytic activity, with a preference for activation of P2Y LPA receptors. The efficacy of the ATX/LPA signaling responses are abrogated more efficiently by tunnel-binding inhibitors, such as ziritaxestat (GLPG1690), compared with inhibitors that exclusively target the active site, as shown in primary lung fibroblasts and a murine model of radiation-induced pulmonary fibrosis. Our results uncover a receptor-selective signaling mechanism for ATX, implying clinical benefit for tunnel-targeting ATX inhibitors.

PubMed: 36640760
DOI: 10.1016/j.chembiol.2022.12.006

実験手法

X-RAY DIFFRACTION (2 Å)