title: The conformation of an inhibitor bound to the gastric proton pump.
abstract: Substituted imidazo[1,2-a]pyridines are pharmaceutically important small molecule inhibitors of the gastric H+/K+-ATPase, the membrane-bound therapeutic target for peptic ulcer disease. A non-perturbing analytical technique, rotational resonance NMR spectroscopy, was used to measure a precise (to +/-0.2 A) distance between atomic sites in a substituted imidazo[1,2-a]pyridine, TMPIP, bound to H+/K+-ATPase at its high-affinity site in the intact, native membrane. The structural analysis of the enzyme-inhibitor complex revealed that the flexible moiety of TMPIP adopts a 'syn-type' conformation at its site of action. Hence, the conformation of an inhibitor has been resolved directly under near-physiological conditions, providing a sound experimental basis for rational design of many active compounds of pharmaceutical interest. Chemically restraining the flexible moiety of compounds like TMPIP in the syn-type binding conformation was found to increase activity by over 2 orders of magnitude. Such information is normally only available after extensive synthesis of related compounds and multiple screening approaches.
authors.affiliation: Department of Biochemistry, University of Oxford, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Middleton
authors.forename: R
authors.initials: R
authors.lastname: Robins
authors.forename: X
authors.initials: X
authors.lastname: Feng
authors.forename: M H
authors.initials: MH
authors.lastname: Levitt
authors.forename: I D
authors.initials: ID
authors.lastname: Spiers
authors.forename: C H
authors.initials: CH
authors.lastname: Schwalbe
authors.forename: D G
authors.initials: DG
authors.lastname: Reid
authors.forename: A
authors.initials: A
authors.lastname: Watts
mesh_terms: D017506:H(+)-K(+)-Exchanging ATPase / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D054328:Proton Pump Inhibitors; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism; D013270:Stomach / Q000201:enzymology*
chemical_list: D054328:Proton Pump Inhibitors; D011725:Pyridines; D017506:H(+)-K(+)-Exchanging ATPase; C001439:imidazo(1,2-a)pyridine