The conformation of an inhibitor bound to the gastric proton pump.
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.
Middleton
D A
DA
Department of Biochemistry, University of Oxford, UK.
Robins
R
R
Feng
X
X
Levitt
M H
MH
Spiers
I D
ID
Schwalbe
C H
CH
Reid
D G
DG
Watts
A
A
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*
D054328:Proton Pump Inhibitors; D011725:Pyridines; D017506:H(+)-K(+)-Exchanging ATPase; C001439:imidazo(1,2-a)pyridine