Crystal structures of the gastric proton pump

被引：90
作者：
Abe, Kazuhiro [1 ,2 ,3 ]
Irie, Katsumasa [1 ,2 ]
Nakanishi, Hanayo [1 ,3 ]
Suzuki, Hiroshi [4 ]
Fujiyoshi, Yoshinori [1 ,3 ,5 ]
机构：
[1] Nagoya Univ, Cellular & Struct Physiol Inst, Nagoya, Aichi, Japan
[2] Nagoya Univ, Grad Sch Pharmaceut Sci, Nagoya, Aichi, Japan
[3] Japan Sci & Technol Corp, Japan Core Res Evolut Sci & Technol, Nagoya, Aichi, Japan
[4] Rockefeller Univ, Lab Mol Electron Microscopy, 1230 York Ave, New York, NY 10021 USA
[5] CeSPIA Inc, Tokyo, Japan
来源：
NATURE | 2018年 / 556卷 / 7700期
关键词：
ADP-INSENSITIVE PHOSPHOENZYME; K+-BINDING-SITE; ION-TRANSPORT; SALT BRIDGE; ATPASE; H+; K+-ATPASE; MECHANISM; ACID; NA; K-ATPASE; CA2+-ATPASE;
D O I：
10.1038/s41586-018-0003-8
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
The gastric proton pump-the H+, K+-ATPase-is a P-type ATPase responsible for acidifying the gastric juice down to pH 1. This corresponds to a million-fold proton gradient across the membrane of the parietal cell, the steepest known cation gradient of any mammalian tissue. The H+, K+-ATPase is an important target for drugs that treat gastric acid-related diseases. Here we present crystal structures of the H+, K+-ATPase in complex with two blockers, vonoprazan and SCH28080, in the luminal-open state, at 2.8 angstrom resolution. The drugs have partially overlapping but clearly distinct binding modes in the middle of a conduit running from the gastric lumen to the cation-binding site. The crystal structures suggest that the tight configuration at the cation-binding site lowers the pK(a) value of Glu820 sufficiently to enable the release of a proton even into the pH 1 environment of the stomach.
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页码：214 / +
页数：16
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