Journal
NATURE
Volume 556, Issue 7700, Pages 214-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0003-8
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Funding
- CREST from JST [JPMJCR14M4]
- Basis for Supporting Innovative Drug Discovery and Life Science Research
- Japan New Energy and Industrial Technology Development Organization (NEDO)
- Japan Agency for Medical Research and Development (AMED)
- Grants-in-Aid for Scientific Research [15H05775] Funding Source: KAKEN
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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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