Conformation-Dependent Inhibition of Gastric H1,K1-ATPase by SCH 28080 Demonstrated by Mutagenesis of Glutamic Acid 820

Gastric H1,K1-ATPase can be inhibited by imidazo pyridines like 2-methyl-8-[phenylmethoxy] imidazo-(1,2a) pyridine 3-ace-tonitrile (SCH 28080). The drug shows a high affinity for inhibi-tion of K1-activated ATPase and for prevention of ATP phos-phorylation. The inhibition by SCH 28080 can be explained by assuming that SCH 28080 binds to both the E2 and the phos-phorylated intermediate (E2-P) forms of the enzyme. We ob-served recently that some mutants, in which glutamic acid 820 present in transmembrane domain six of the catalytic subunit had been replaced (E820Q, E820N, E820A), lost their K1-sen-sitivity and showed constitutive ATPase activity. This ATPase activity could be inhibited by similar SCH 28080 con-centrations as the K1-activated ATPase of the wild-type en-zyme. SCH 28080 also inhibited ATP phosphorylation at 21°