7W48
Crystal structure of the gastric proton pump complexed with PF-03716556
Summary for 7W48
| Entry DOI | 10.2210/pdb7w48/pdb |
| Descriptor | Potassium-transporting ATPase alpha chain 1, Potassium-transporting ATPase subunit beta, MAGNESIUM ION, ... (8 entities in total) |
| Functional Keywords | cation pump, p-type atpase, gastric, proton pump, membrane protein, p-cab, hydrolase |
| Biological source | Sus scrofa (Pig) More |
| Total number of polymer chains | 2 |
| Total formula weight | 150774.01 |
| Authors | Abe, K.,Tanaka, S. (deposition date: 2021-11-26, release date: 2022-01-05, Last modification date: 2024-10-09) |
| Primary citation | Tanaka, S.,Morita, M.,Yamagishi, T.,Madapally, H.V.,Hayashida, K.,Khandelia, H.,Gerle, C.,Shigematsu, H.,Oshima, A.,Abe, K. Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump. J.Med.Chem., 65:7843-7853, 2022 Cited by PubMed 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. PubMed: 35604136DOI: 10.1021/acs.jmedchem.2c00338 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.5 Å) |
Structure validation
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