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Doan, BT ; Fraternali, F ; Do, QT ; Atkinson, RA ; Palmas, P ; Sklenar, V ; Wildgoose, P ; Strop, P ; Saudek, V

A NMR and MD study of the active site of factor Xa by selective inhibitors

Journal de Chimie Physique et de Physico-Chimie Biologique 95 (2) 443-446

par Administrateur - publié le

Abstract :

The structure of two selective inhibitors obtained by the screening of a vast combinatorial library, Ac-Tyr-Ile-Arg-Ile-NH2 and Ac-(4-amino-Phe)-(Cyc.-Gly)NH2, in the active site of the blood clotting enzyme factor Xa was determined using transferred NOE NMR and simulated annealing (SA) under NMR constraints. The refined structures of the inhibitors were docked in the active site and SA was performed inside the enzyme which has been kept as a rigid charged template. The final structures were optimised by molecular dynamics simulation of the complexes in water. The inhibitors assume a compact, very well defined conformation embedded in the binding site without blocking the catalysis. The model allows to explain the mode of action, affinity and specificity.