Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump
Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump
复制标题
钾竞争性酸阻滞剂与胃质子泵结合的结构基础
DOI：
10.1021/acs.jmedchem.2c00338
复制
发表时间：
2022
影响因子：
7.3
通讯作者：
Abe Kazuhiro
中科院分区：
文献类型：
--
作者：
Tanaka Saki;Morita Mikio;Yamagishi Tatsuya;Madapally Hridya Valia;Hayashida Kenichi;Khandelia Himanshu;Gerle Christoph;Shigematsu Hideki;Oshima Atsunori;Abe Kazuhiro
作为胃质子泵的特异性抑制剂，K+竞争性酸阻断剂（P-CAB）近年来在亚洲被用于胃酸相关疾病的临床治疗。然而，由于这些化合物是基于表型筛选开发的，因此其详细的结合位姿是未知的。我们显示了与四种不同的P-CAB（替戈拉赞、索拉拉赞、PF-03716556和revaprazan）复合的胃质子泵的晶体和冷冻电镜结构，分辨率达到2.8 μ m。这些结构描述了它们相互作用的分子细节，并得到突变功能分析和分子动力学模拟的支持。我们揭示了revaprazan具有一种新的结合模式，其中其四氢异喹啉部分结合在阳离子传输管道的深处。这些P-CAB的作用机制现在可以在分子水平上进行评估，这将有助于合理开发和改进目前可用的P-CAB，以提供更好的治疗酸相关胃肠道疾病。
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.