Crystal structure of equine serum albumin in complex with cetirizine reveals a novel drug binding site |
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| Affiliation: | 1. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA;2. New York Structural Genomics Research Consortium (NYSGRC), USA;3. Faculty of Physics, Warsaw University of Technology, 00-662 Warszawa, Poland;1. KininX SAS, Grenoble, France;2. Internal medicine department, Saint Antoine Hospital, AP-HP, DHU i2B, Paris 6 University, Paris, France;3. Centre de Référence des Angioedèmes CREAK, CHU Grenoble, CHU Angers and AP-HP, Paris, France;4. L’UNAM Université, Dermatology department, University Hospital, Angers, France;5. CHU Grenoble, Laboratoire d’Immunologie, Grenoble, France;6. Université Joseph Fourier, GREPI EA-UJF 7408, Grenoble, France;1. Division of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan;2. Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan;1. University of Guanajuato, Leon Guanajuato, Mexico;2. Research Department, Hospital Regional de Alta Especialidad del Bajio, Leon Guanajuato, Mexico;1. Department of Chemistry, Payame Noor University, PO Box 19395-3697 Teheran, Iran;2. Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran;1. Physics Department, Princeton University, Princeton, NJ 08544, USA;2. Joint Institute for Nuclear Research, Dubna 141980, Russia;3. Dipartimento di Fisica, Università degli Studi e INFN, Milano 20133, Italy;4. Amherst Center for Fundamental Interactions and Physics Department, University of Massachusetts, Amherst, MA 01003, USA;5. APC, Univ. Paris Diderot, CNRS/IN2P3, CEA/Irfu, Obs. de Paris, Sorbonne Paris Cité, France;6. Dipartimento di Fisica, Università e INFN, Genova 16146, Italy;7. Physics Department, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA;8. INFN Laboratori Nazionali del Gran Sasso, Assergi 67010, Italy;9. Department of Physics, Technische Universität Dresden, 01062 Dresden, Germany;10. National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), 115409 Moscow, Russia;11. NRC Kurchatov Institute, Moscow 123182, Russia;12. M. Smoluchowski Institute of Physics, Jagiellonian University, Krakow, 30059, Poland;13. Physics and Astronomy Department, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA;14. Institut für Experimentalphysik, Universität Hamburg, Germany;15. Physik Department, Technische Universität München, Garching 85747, Germany;p. Max-Plank-Institut für Kernphysik, Heidelberg 69029, Germany;q. Dipartimento di Chimica, Università e INFN, Perugia 06123, Italy;r. St. Petersburg Nuclear Physics Institute, Gatchina 188350, Russia;s. Department of Physics, University of Houston, Houston, TX 77204, USA;t. Kiev Institute for Nuclear Research, Kiev 06380, Ukraine;u. Lomonosov Moscow State University Skobeltsyn Institute of Nuclear Physics, Moscow 119234, Russia;v. Chemical Engineering Department, Princeton University, Princeton, NJ 08544, USA;w. Gran Sasso Science Institute (INFN), 67100 L''Aquila, Italy;x. Institut für Physik, Johannes Gutenberg Universität Mainz, 55122 Mainz, Germany;1. Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212013, PR China;2. Department of Clinical Laboratory and Hematology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China |
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| 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 2.1 Å. 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. |
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| Keywords: | Serum albumin Cetirizine Zyrtec Drugs Binding pockets Crystal structure |
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