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TitleStructural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump.
Journal, issue, pagesJ Med Chem, Vol. 65, Issue 11, Page 7843-7853, Year 2022
Publish dateJun 9, 2022
AuthorsSaki Tanaka / Mikio Morita / Tatsuya Yamagishi / Hridya Valia Madapally / Kenichi Hayashida / Himanshu Khandelia / Christoph Gerle / Hideki Shigematsu / Atsunori Oshima / Kazuhiro Abe /
PubMed AbstractAs 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- ...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.
External linksJ Med Chem / PubMed:35604136
MethodsEM (single particle) / X-ray diffraction
Resolution2.76 - 3.5 Å
Structure data

32299

7w4a

EMDB-32299, PDB-7w4a:
Cryo-EM structure of the gastric proton pump complexed with revaprazan
Method: EM (single particle) / Resolution: 2.76 Å

PDB-7w47:
Crystal structure of the gastric proton pump complexed with tegoprazan
Method: X-RAY DIFFRACTION / Resolution: 3.0 Å

PDB-7w48:
Crystal structure of the gastric proton pump complexed with PF-03716556
Method: X-RAY DIFFRACTION / Resolution: 3.5 Å

PDB-7w49:
Crystal structure of the gastric proton pump complexed with soraprazan
Method: X-RAY DIFFRACTION / Resolution: 3.1 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-RB:
RUBIDIUM ION / Rubidium

ChemComp-8BN:
Tegoprazan

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-HOH:
WATER / Water

ChemComp-CE1:
O-DODECANYL OCTAETHYLENE GLYCOL / Octaethylene glycol monododecyl ether

ChemComp-8BZ:
N-(2-hydroxyethyl)-N,2-dimethyl-8-[[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino]imidazo[1,2-a]pyridine-6-carboxamide

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

ChemComp-8CE:
Soraprazan

ChemComp-8CK:
N-(4-fluorophenyl)-4,5-dimethyl-6-[(1R)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]pyrimidin-2-amine

ChemComp-NA:
Unknown entry

Source
  • sus scrofa (pig)
KeywordsHYDROLASE / Cation pump / P-type ATPase / gastric / proton pump / membrane protein / P-CAB

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