PDBsum entry 1e7b

Carrier protein

PDB id: 1e7b

Contents

Protein chain

578 a.a. *

Ligands

HLT ×6

Waters ×57

* Residue conservation analysis

References listed in PDB file

Key reference

Title

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

Authors

A.A.Bhattacharya, S.Curry, N.P.Franks.

Ref.

J Biol Chem, 2000, 275, 38731-38738. [DOI no: 10.1074/jbc.M005460200]

PubMed id

10940303

Abstract

Human serum albumin (HSA) is one of the most abundant proteins in the circulatory system and plays a key role in the transport of fatty acids, metabolites, and drugs. For many drugs, binding to serum albumin is a critical determinant of their distribution and pharmacokinetics; however, there have as yet been no high resolution crystal structures published of drug-albumin complexes. Here we describe high resolution crystal structures of HSA with two of the most widely used general anesthetics, propofol and halothane. In addition, we describe a crystal structure of HSA complexed with both halothane 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 inhalational agent halothane binds (at concentrations in the pharmacologically relevant range) at three sites that are also fatty acid binding loci. At much higher halothane concentrations, we have identified additional sites that are occupied. All of the higher affinity anesthetic binding sites are amphiphilic in nature, with both polar and apolar parts, and anesthetic binding causes only minor changes in local structure.

Figure 2.
Fig. 2. The propofol binding sites on HSA. A, HSA with propofol showing the locations of the two propofol binding sites. Site PR1, which is within sub-domain IIIA (B), and site PR2, which is within sub-domain IIIB (C) are shown. The dashed lines represent hydrogen bonds. The difference electron density is an F[o] F[c] omit map calculated at 4 . The amino acid side chains that are close to the propofol molecules are shown as ball and stick models (a complete list is given in Table III).

Figure 4.
Fig. 4. Details of halothane binding sites. A, halothane binding sites at the interface between subdomains IIA and IIB. B, halothane site in subdomain IIIA. C, halothane sites in subdomain IIA. D, halothane site at the interface between subdomains IA and IIA. The difference electron density is an F[o] F[c] omit map calculated at 4 . Some of the amino acid side chains that are close to the halothane molecules are shown as ball and stick models (a complete list is given in Table IV). Note that in D only 11 of the 14 carbon atoms of myristate are shown because, due to disorder, the terminal carbons were not observed in the electron density map.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2000, 275, 38731-38738) copyright 2000.