6LEH

Crystal structure of Autotaxin in complex with an inhibitor

6LEH の概要

• エントリーDOI: 10.2210/pdb6leh/pdb
• 分子名称: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, 1,2-ETHANEDIOL, ethyl 2-[2-(4-chlorophenyl)-7-methyl-5-oxidanylidene-imidazo[1,2-a]pyrimidin-8-yl]ethanoate, ... (12 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 99672.37

構造登録者

Nishimasu, H.,Osamu, N. (登録日: 2019-11-25, 公開日: 2020-03-18, 最終更新日: 2023-11-22)

主引用文献

Kawaguchi, M.,Okabe, T.,Okudaira, S.,Hama, K.,Kano, K.,Nishimasu, H.,Nakagawa, H.,Ishitani, R.,Kojima, H.,Nureki, O.,Aoki, J.,Nagano, T.
Identification of PotentIn VivoAutotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain.
J.Med.Chem., 63:3188-3204, 2020

PubMed Abstract: Autotaxin (ATX, also known as ENPP2) is a predominant lysophosphatidic acid (LPA)-producing enzyme in the body, and LPA regulates various physiological functions, such as angiogenesis and wound healing, as well as pathological functions, including proliferation, metastasis, and fibrosis, via specific LPA receptors. Therefore, the ATX-LPA axis is a promising therapeutic target for dozens of diseases, including cancers, pulmonary and liver fibroses, and neuropathic pain. Previous structural studies revealed that the catalytic domain of ATX has a hydrophobic pocket and a hydrophobic channel; these serve to recognize the substrate, lysophosphatidylcholine (LPC), and deliver generated LPA to LPA receptors on the plasma membrane. Most reported ATX inhibitors bind to either the hydrophobic pocket or the hydrophobic channel. Herein, we present a unique ATX inhibitor that binds mainly to the hydrophobic pocket and also partly to the hydrophobic channel, inhibiting ATX activity with high potency and selectivity and . Notably, our inhibitor can rescue the cardia bifida (two hearts) phenotype in ATX-overexpressing zebrafish embryos.

PubMed: 32134652
DOI: 10.1021/acs.jmedchem.9b01967

実験手法

X-RAY DIFFRACTION (2 Å)