Crystal structure analysis of warfarin binding to human serum albumin - Anatomy of drug site I

Human serum albumin (HSA) is an abundant transport protein found in plasma that binds a wide variety of drugs in two primary binding sites (I and II) and can have a significant impact on their pharmacokinetics. We have determ ined the crystal structures at 2.5 Angstrom -resolution of HSA-myristate co mplexed with the R-(+) and S-(-) enantiomers of warfarin, a widely used ant icoagulant that binds to the protein with high affinity. The structures con firm that warfarin binds to drug site I (in subdomain IIA) in the presence of fatty acids and reveal the molecular details of the protein drug interac tion. The two enantiomers of warfarin adopt very similar conformations when bound to the protein and make many of the same specific contacts with amin o acid side chains at the binding site, thus accounting for the relative la ck of stereospecificity of the HSA-warfarin interaction. The conformation o f the warfarin binding pocket is significantly altered upon binding of fatt y acids, and this can explain the observed enhancement of warfarin binding to HSA at low levels of fatty acid.