7W49

Crystal structure of the gastric proton pump complexed with soraprazan

7W49 の概要

• エントリーDOI: 10.2210/pdb7w49/pdb
• 分子名称: Potassium-transporting ATPase alpha chain 1, Potassium-transporting ATPase subunit beta, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: cation pump, p-type atpase, gastric, proton pump, membrane protein, p-cab, hydrolase
• 由来する生物種: Sus scrofa (Pig); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 148796.88

構造登録者

Abe, K.,Tanaka, S. (登録日: 2021-11-26, 公開日: 2022-01-05, 最終更新日: 2024-11-13)

主引用文献

Tanaka, S.,Morita, M.,Yamagishi, T.,Madapally, H.V.,Hayashida, K.,Khandelia, H.,Gerle, C.,Shigematsu, H.,Oshima, A.,Abe, K.
Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump.
J.Med.Chem., 65:7843-7853, 2022

PubMed Abstract: As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases.

PubMed: 35604136
DOI: 10.1021/acs.jmedchem.2c00338

実験手法

X-RAY DIFFRACTION (3.1 Å)