Crystal structures of the gastric proton pump

Kazuhiro Abe, Katsumasa Irie, Hanayo Nakanishi, Hiroshi Suzuki, Yoshinori Fujiyoshi

Index: 10.1038/s41586-018-0003-8

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Abstract

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 Å 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 pKa value of Glu820 sufficiently to enable the release of a proton even into the pH 1 environment of the stomach.