Crystal structures of the gastric proton pump

Nature. 2018 Apr;556(7700):214-218. doi: 10.1038/s41586-018-0003-8. Epub 2018 Apr 4.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cations, Monovalent / metabolism
  • Crystallography, X-Ray
  • H(+)-K(+)-Exchanging ATPase / chemistry*
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Models, Molecular
  • Potassium / metabolism
  • Protein Binding
  • Proton Pump Inhibitors / chemistry
  • Proton Pump Inhibitors / pharmacology
  • Protons
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Rabbits
  • Stomach / enzymology*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Swine

Substances

  • 1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine
  • Cations, Monovalent
  • Imidazoles
  • Proton Pump Inhibitors
  • Protons
  • Pyrroles
  • Sulfonamides
  • Sch 28080
  • H(+)-K(+)-Exchanging ATPase
  • Potassium