Binding of the general anesthetics propofol and halothane to human serum albumin - High resolution crystal structures

Human serum albumin (HSA) is one of the most abundant proteins in the circu latory system and plays a key role in the transport of fatty acids, metabol ites, and drugs. For many drugs, binding to serum albumin is a critical det erminant of their distribution and pharmacokinetics; however, there have as yet been no high resolution crystal structures published of drug-albumin c omplexes. Here we describe high resolution crystal structures of HSA with t wo of the most widely used general anesthetics, propofol and halothane. In addition, we describe a crystal structure of HSA complexed with both haloth ane and the fatty acid, myristate. We show that the intravenous anesthetic propofol binds at two discrete sites on HSA in preformed pockets that have been shown to accommodate fatty acids. Similarly we show that the inhalatio nal agent halothane binds (at concentrations in the pharmacologically relev ant range) at three sites that are also fatty acid binding loci. At much hi gher halothane concentrations, we have identified additional sites that are occupied, All of the higher affinity anesthetic binding sites are amphiphi lic in nature, with both polar and apolar parts, and anesthetic binding cau ses only minor changes in local structure.