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The conformation of an inhibitor bound to the gastric proton pump
Author(s) -
Middleton David A.,
Robins Rachel,
Feng Xiaolong,
Levitt Malcolm H.,
Spiers Ian D.,
Schwalbe Carl H.,
Reid David G.,
Watts Anthony
Publication year - 1997
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(97)00525-5
Subject(s) - moiety , chemistry , rational design , stereochemistry , pyridine , nuclear magnetic resonance spectroscopy , atpase , small molecule , enzyme , active site , biochemistry , nanotechnology , organic chemistry , materials science
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 Å) 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.