Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to human serum albumin

Human serum albumin (HSA) is an abundant plasma protein that is responsible for the transport of fatty acids. HSA also binds and perturbs the pharmaco kinetics of a wide range of drug compounds. Binding studies have revealed s ignificant interactions between fatty acid and drug-binding sites on albumi n but high-resolution structural information on ligand binding to the prote in has been lacking. We report here a crystallographic study of five HSA-fa tty acid complexes formed using saturated medium-chain and long-chain fatty acids (C10:0, C12:0,C14:0, C16:0 and C18:0). A total of seven binding site s that are occupied by all medium-chain and long-chain fatty acids have bee n identified, although medium-chain fatty acids are found to bind at additi onal sites on the protein, yielding a total of 11 distinct binding location s. Comparison of the different complexes reveals key similarities and signi ficant differences in the modes of binding, and serves to rationalise much of the biochemical data on fatty acid interactions with albumin. The two pr incipal drug-binding sites, in sub-domains IIA and IIIA, are observed to be occupied by fatty acids and one of them (in IIIA) appears to coincide with a high-affinity long-chain fatty acid binding site. (C) 2000 Academic Pres s.