2. Academic Validation
  3. 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

  • J Med Chem. 2022 Jun 9;65(11):7843-7853. doi: 10.1021/acs.jmedchem.2c00338.
Saki Tanaka 1,  Mikio Morita 2 3,  Tatsuya Yamagishi 2 3,  Hridya Valia Madapally 4,  Kenichi Hayashida 5,  Himanshu Khandelia 4,  Christoph Gerle 6 7,  Hideki Shigematsu 6,  Atsunori Oshima 1 5 8,  Kazuhiro Abe 1 5
Affiliations

Affiliations

  • 1 Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, 464-8601, Japan.
  • 2 Discovery Research, RaQualia Pharma Inc., 1-21-19 Meieki Minami, Nakamura, Nagoya 450-0003, Japan.
  • 3 RaQualia Pharma Industry-Academia Collaborative Research Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
  • 4 PHYLIFE: Physical Life Science, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
  • 5 Cellular and Structural Physiology Institute, Nagoya University, Nagoya, 464-8601, Japan.
  • 6 RIKEN SPring-8 Center, Kouto, Sayo-gun, Hyogo 679-5148, Japan.
  • 7 Laboratory for Protein Crystallography, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
  • 8 Institute for Glyco-core Research (iGCORE), Nagoya University, Nagoya, 464-8601, Japan.
PMID: 35604136 DOI: 10.1021/acs.jmedchem.2c00338
Abstract

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.

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