8C3P

Crystal structure of autotaxin gamma in complex with LPA 18:1

8C3P の概要

• エントリーDOI: 10.2210/pdb8c3p/pdb
• 分子名称: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 7alpha-hydroxycholesterol, ... (9 entities in total)
• 機能のキーワード: lipid, lpa, co-crystal, ectonucleotide pyrophosphatase/phosphodiesterase (enpp), hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 209570.57

構造登録者

Eymery, M.C.,McCarthy, A.A. (登録日: 2022-12-28, 公開日: 2023-11-22, 最終更新日: 2024-11-20)

主引用文献

Eymery, M.C.,Nguyen, K.A.,Basu, S.,Hausmann, J.,Tran-Nguyen, V.K.,Seidel, H.P.,Gutierrez, L.,Boumendjel, A.,McCarthy, A.A.
Discovery of potent chromone-based autotaxin inhibitors inspired by cannabinoids.
Eur.J.Med.Chem., 263:115944-115944, 2023

PubMed Abstract: Autotaxin (ATX) is an enzyme primarily known for the production of lysophosphatidic acid. Being involved in the development of major human diseases, such as cancer and neurodegenerative diseases, the enzyme has been featured in multiple studies as a pharmacological target. We previously found that the cannabinoid tetrahydrocannabinol (THC) could bind and act as an excellent inhibitor of ATX. This study aims to use the cannabinoid scaffold as a starting point to find cannabinoid-unrelated ATX inhibitors, following a funnel down approach in which large chemical libraries sharing chemical similarities with THC were screened to identify lead scaffold types for optimization. This approach allowed us to identify compounds bearing chromone and indole scaffolds as promising ATX inhibitors. Further optimization led to MEY-003, which is characterized by the direct linkage of an N-pentyl indole to the 5,7-dihydroxychromone moiety. This molecule has potent inhibitory activity towards ATX-β and ATX-ɣ as evidenced by enzymatic studies and its mode of action was rationalized by structural biology studies using macromolecular X-ray crystallography.

PubMed: 37976710
DOI: 10.1016/j.ejmech.2023.115944

実験手法

X-RAY DIFFRACTION (2.38 Å)