| Abstract
| - Using the recent high-resolution X-ray structures determined for the Ca2+-ATPase, we havegenerated two homology models of the gastric H+/K+-ATPase reflecting the E1 and E2conformations adopted by P-type ATPases in their catalytic cycle. In regimes where the in situsolid-state NMR-determined structure for 1,2,3-trimethyl-8-(pentafluorophenylmethoxy)imidazo[1,2-a]pyridinium iodide (TMPFPIP), a reversible inhibitor of the gastric H+/K+-ATPase,was retained in its predefined conformation and was allowed full torsional flexibility in docking,the ligands localized to discrete binding volumes in the E1 model and to a single central bindingspace, together with secondary peripheral locations, in the E2 conformation. The results ofthese binding studies are in good agreement with current site-directed mutagenesis data andsupport the suggestion that the binding site is proximal to the loop between TM5 and TM6and TM8, the transmembrane (TM) region considered important for cation translocation.Furthermore, the results of the simulation with the flexible ligand complement the solid-stateNMR structural constraints of this inhibitor when bound in situ to the protein.
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