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J. Biol. Chem., Vol. 276, Issue 25, 22804-22809, June 22, 2001
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From the Biophysics Section, Blackett Laboratory, Imperial College
of Science, Technology, and Medicine, London SW7 2BW, United Kingdom
and the ¶ School of Biological Sciences, University of
Southampton, Biomedical Sciences Building, Bassett, Crescent East,
Southampton SO16 7PX, United Kingdom
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 determined the crystal structures at
2.5 Å-resolution of HSA-myristate complexed with the R-(+) and S-( The atomic coordinates and the structure factors (code 1h9z and 1ha2) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
Crystal Structure Analysis of Warfarin Binding to Human
Serum Albumin
ANATOMY OF DRUG SITE I*
§,
) enantiomers of warfarin, a widely used
anticoagulant that binds to the protein with high affinity. The
structures confirm 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 interaction. The two enantiomers of warfarin adopt
very similar conformations when bound to the protein and make many of
the same specific contacts with amino acid side chains at the binding
site, thus accounting for the relative lack of stereospecificity of the
HSA-warfarin interaction. The conformation of the warfarin binding
pocket is significantly altered upon binding of fatty acids, and this
can explain the observed enhancement of warfarin binding to HSA at low
levels of fatty acid.
*
This work was funded by grant support from the
Biotechnological and Biological Sciences Research Council, UK.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a Ph.D. studentship from the Medical Research
Council, UK.
§
Present address: The Burnham Inst., 10901 N. Torrey Pines Rd., La
Jolla, CA 92037.
To whom correspondence should be addressed. Tel.:
44-20-7594-7632; Fax: 44-20-7589-0191; E-mail: s.curry@ic.ac.uk.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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