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.