Molecular modeling of SCH28080 binding to the gastric H,K-ATPase and MgATP interactions with SERCA- and Na,K-ATPases.

We have used homology molecular modeling based on the srCaATPase E(2) conformation, pdb1kju, to predict side chains involved in docking the K(+) competitive inhibitor, SCH28080, to the H,K-ATPase. A model for SCH28080 binding between residues L809 and A335 in the same space utilized by omeprazole is proposed. We also describe modeling MgATP binding to the E(1) structure of the srATPase, pdb1eul, as a paradigm for the Na,K- and H,K-ATPases. The resulting model, E(1).MgATP, visualizes a conformation not yet available by crystallization and successfully predicts a range of published results, including backbone cleavages near V440 (N domain) and V712 (P domain) mediated by FeATP in the Na,K-ATPase. A separate model for MgATP docked to E(2) (pdb1kju) shows that access of the gamma phosphate to D351 is blocked by the A domain. The E(2). MgATP model explains FeATP-mediated cleavages of the Na,K-ATPase near V440 and E214 (A domain) and homologous results in the H,K-ATPase.