Analysis of the gastric H,K ATPase for ion pathways and inhibitor binding sites.

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Munson K, Law RJ, Sachs G

Analysis of the gastric H,K ATPase for ion pathways and inhibitor binding sites.

Biochemistry. 2007 May 8;46(18):5398-417. doi: 10.1021/bi062305h. Epub 2007 Apr 11.

PubMed ID

17425287 [ View in PubMed

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Abstract

New models of the gastric H,K ATPase in the E1K and E2P states are presented as the first structures of a K+ counter-transport P2-type ATPase exhibiting ion entry and exit paths. Homology modeling was first used to generate a starting conformation from the srCa ATPase E2P form (PDB code 1wpg) that contains bound MgADP. Energy minimization of the model showed a conserved adenosine site but nonconserved polyphosphate contacts compared to the srCa ATPase. Molecular dynamics was then employed to expand the luminal entry sufficiently to allow access of the rigid K+ competitive naphthyridine inhibitor, Byk99, to its binding site within the membrane domain. The new E2P model had increased separation between transmembrane segments M3 through M8, and addition of water in this space showed not only an inhibitor entry path to the luminal vestibule but also a channel leading to the ion binding site. Addition of K+ to the hydrated channel with molecular dynamics modeling of ion movement identified a pathway for K+ from the lumen to the ion binding site to give E2K. A K+ exit path to the cytoplasm operating during the normal catalytic cycle is also proposed on the basis of an E1K homology model derived from the E12Ca2+ form of the srCa ATPase (PDB code 1su4). Autodock analyses of the new E2P model now correctly discriminate between high- and low-affinity K+ competitive inhibitors. Finally, the expanded luminal vestibule of the E2P model explains high-affinity ouabain binding in a mutant of the H,K ATPase [Qiu et al. (2005) J. Biol. Chem. 280, 32349-32355].

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Omeprazole	Potassium-transporting ATPase alpha chain 1	Protein	Humans	Yes	Inhibitor	Details