title: Crystal structure of equine serum albumin in complex with cetirizine reveals a novel drug binding site.
abstract: Serum albumin (SA) is the main transporter of drugs in mammalian blood plasma. Here, we report the first crystal structure of equine serum albumin (ESA) in complex with antihistamine drug cetirizine at a resolution of 2.1Å. Cetirizine is bound in two sites--a novel drug binding site (CBS1) and the fatty acid binding site 6 (CBS2). Both sites differ from those that have been proposed in multiple reports based on equilibrium dialysis and fluorescence studies for mammalian albumins as cetirizine binding sites. We show that the residues forming the binding pockets in ESA are highly conserved in human serum albumin (HSA), and suggest that binding of cetirizine to HSA will be similar. In support of that hypothesis, we show that the dissociation constants for cetirizine binding to CBS2 in ESA and HSA are identical using tryptophan fluorescence quenching. Presence of lysine and arginine residues that have been previously reported to undergo nonenzymatic glycosylation in CBS1 and CBS2 suggests that cetirizine transport in patients with diabetes could be altered. A review of all available SA structures from the PDB shows that in addition to the novel drug binding site we present here (CBS1), there are two pockets on SA capable of binding drugs that do not overlap with fatty acid binding sites and have not been discussed in published reviews.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA; New York Structural Genomics Research Consortium (NYSGRC), USA.
authors.forename: Katarzyna B
authors.initials: KB
authors.lastname: Handing
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA; New York Structural Genomics Research Consortium (NYSGRC), USA.
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Shabalin
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA; Faculty of Physics, Warsaw University of Technology, 00-662 Warszawa, Poland.
authors.forename: Karol
authors.initials: K
authors.lastname: Szlachta
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA; New York Structural Genomics Research Consortium (NYSGRC), USA.
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Majorek
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA; New York Structural Genomics Research Consortium (NYSGRC), USA. Electronic address: wladek@iwonka.med.virginia.edu.
authors.forename: Wladek
authors.initials: W
authors.lastname: Minor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D017332:Cetirizine / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D039563:Histamine H1 Antagonists, Non-Sedating / Q000737:chemistry / Q000378:metabolism; D006736:Horses; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D039563:Histamine H1 Antagonists, Non-Sedating; D012709:Serum Albumin; D017332:Cetirizine
keywords: Binding pockets; Cetirizine; Crystal structure; Drugs; Serum albumin; Zyrtec