Structural Basis of the Drug-binding Specificity of Human Serum Albumin
Abstract
Human serum albumin (HSA) is an abundant plasma protein that binds a remarkably wide range of drugs, thereby restricting their free, active concentrations. The problem of overcoming the binding affinity of lead compounds for HSA represents a major challenge in drug development. Crystallographic analysis of 17 different complexes of HSA with a wide variety of drugs and small-molecule toxins reveals the precise architecture of the two primary drug-binding sites on the protein, identifying residues that are key determinants of binding specificity and illuminating the capacity of both pockets for flexible accommodation. Numerous secondary binding sites for drugs distributed across the protein have also been identified. The binding of fatty acids, the primary physiological ligand for the protein, is shown to alter the polarity and increase the volume of drug site 1. These results clarify the interpretation of accumulated drug binding data and provide a valuable template for design efforts to modulate the interaction with HSA.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Albumin has a free thiol at Cysteine 34 that can scavenge hydroxyl radicals due to the large albumin pool in the body.
“Also, albumin has a free thiol at the Cysteine 34 place, which in free form has a significant capacity to scavenge hydroxyl radicals due to the large albumin pool in the body.93”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [93]
Cites
The PyMOL Molecular Graphics System
DeLano, W. L. (2002) · Medical Entomology and Zoology · Cited by 18,147 · see citing works
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,299 · see citing works
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,720 · see citing works
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,650 · see citing works
Atomic structure and chemistry of human serum albumin
He, X. M., & Carter, D. C. (1992) · Nature · doi:10.1038/358209a0 · Cited by 3,833 · see citing works
All About Albumin: Biochemistry, Genetics, and Medical Applications
Peters, T. (1995) · Thammasat University Digital Collections · Cited by 3,089 · see citing works
The Characterization of Two Specific Drug Binding Sites on Human Serum Albumin
Sudlow, G., Birkett, D. J., & WADE, D. N. (1975) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)10691-3 · Cited by 1,738 · see citing works
Further Characterization of Specific Drug Binding Sites on Human Serum Albumin
Sudlow, G., Birkett, D. J., & WADE, D. N. (1976) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)10855-9 · Cited by 1,453 · see citing works
Curry, S., Mandelkow, H., Brick, P., & Franks, N. P. (1998) · Nature Structural Biology · doi:10.1038/1869 · Cited by 1,378 · see citing works
Self-citationThe United Kingdom Chemical Database Service
Fletcher, D. A., McMeeking, R. F., & Parkin, D. M. (1996) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci960015+ · Cited by 1,104 · see citing works
Bhattacharya, A. A., Gruene, T., & Curry, S. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.4158 · Cited by 905 · see citing works
Self-citationCrystal Structure Analysis of Warfarin Binding to Human Serum Albumin
Petitpas, I., Bhattacharya, A. A., Twine, S., Malcolm, E. A. S. T., & Curry, S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100575200 · Cited by 827 · see citing works
Self-citationvan Aalten, D. M. F., Bywater, R. P., Findlay, J. B. C., Hendlich, M., Hooft, R. W. W., & Vriend, G. (1996) · Journal of Computer-Aided Molecular Design · doi:10.1007/bf00355047 · Cited by 715 · see citing works
Predicting plasma protein binding of drugs: a new approach
Kratochwil, N. A., Huber, W., Müller, F., Kansy, M., & Gerber, P. R. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01074-2 · Cited by 553 · see citing works
Fast prediction and visualization of protein binding pockets with PASS
Brady, G. P., & Stouten, P. F. W. (2000) · Journal of Computer-Aided Molecular Design · doi:10.1023/a:1008124202956 · Cited by 532 · see citing works
Binding of the General Anesthetics Propofol and Halothane to Human Serum Albumin
Bhattacharya, A. A., Curry, S., & Franks, N. P. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005460200 · Cited by 529 · see citing works
Self-citationCrystal structural analysis of human serum albumin complexed with hemin and fatty acid
Zunszain, P. A., Ghuman, J., Komatsu, T., Tsuchida, E., & Curry, S. (2003) · BMC Structural Biology · doi:10.1186/1472-6807-3-6 · Cited by 509 · see citing works
Self-citationFatty acid binding to human serum albumin: new insights from crystallographic studies
Curry, S., Brick, P., & Franks, N. P. (1999) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(99)00148-1 · Cited by 497 · see citing works
Self-citationPetitpas, I., Gruene, T., Bhattacharya, A. A., & Curry, S. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.5208 · Cited by 487 · see citing works
Self-citationSjöholm, I., Ekman, B., Kober, A., et al. (1979) · PubMed · Cited by 447 · see citing works
ADMET—turning chemicals into drugs
Hodgson, J. (2001) · Nature Biotechnology · doi:10.1038/90761 · Cited by 426 · see citing works
Valko, K. L., Nunhuck, S., Bevan, C., Abraham, M. H., & Reynolds, D. P. (2003) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.10494 · Cited by 346 · see citing works
The Atomic Structure of Human Methemalbumin at 1.9 Å
Wardell, M. R., Wang, Z., Ho, J. X., Robert, J., Rüker, F., Ruble, J. R., & Carter, D. C. (2002) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2002.6540 · Cited by 332 · see citing works
In silico prediction of drug‐binding strengths to human serum albumin
Colmenarejo, G. (2003) · Medicinal Research Reviews · doi:10.1002/med.10039 · Cited by 292 · see citing works
Loun, B., & Hage, D. S. (1994) · Analytical Chemistry · doi:10.1021/ac00093a043 · Cited by 290 · see citing works
Yamasaki, K., Maruyama, T., Kragh‐Hansen, U., et al. (1996) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/0167-4838(96)00013-1 · Cited by 266 · see citing works
Structural basis of albumin–thyroxine interactions and familial dysalbuminemic hyperthyroxinemia
Petitpas, I., Petersen, C. E., Ha, C., Bhattacharya, A. A., Zunszain, P. A., Ghuman, J., Bhagavan, N. V., & Curry, S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1137188100 · Cited by 258 · see citing works
Self-citationCheminformatic Models To Predict Binding Affinities to Human Serum Albumin
Colmenarejo, G., Álvarez-Pedraglio, A. I., & Lavandera, J.-L. (2001) · Journal of Medicinal Chemistry · doi:10.1021/jm010960b · Cited by 255 · see citing works
Preliminary Crystallographic Studies of Four Crystal forms of Serum Albumin
Carter, D. C., Chang, B., Ho, J. X., et al. (1994) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1994.01049.x · Cited by 249 · see citing works
Rich, R. L., Day, Y. S. N., Morton, T. A., et al. (2001) · Analytical Biochemistry · doi:10.1006/abio.2001.5314 · Cited by 244 · see citing works
Hervé, F., Urien, S., Albengres, E., Duché, J.-C., & Tillement, J. P. (1994) · Clinical Pharmacokinetics · doi:10.2165/00003088-199426010-00004 · Cited by 198 · see citing works
Sogami, M., & Foster, J. F. (1968) · Biochemistry · doi:10.1021/bi00846a020 · Cited by 182 · see citing works
Application of hydrogen bonding calculations in property based drug design
Abraham, M. H., Ibrahim, A., Zissimos, A. M., Zhao, Y. H., Comer, J. E. A., & Reynolds, D. P. (2002) · Drug Discovery Today · doi:10.1016/s1359-6446(02)02478-9 · Cited by 181 · see citing works
Analytical and production seeding techniques
Stura, E. A., & Wilson, I. A. (1990) · Methods · doi:10.1016/s1046-2023(05)80145-8 · Cited by 144 · see citing works
Fehske, K. J., Schläfer, U., Wollert, U., et al. (1982) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)14614-2 · Cited by 136 · see citing works
Characterization of Binding Site of Uremic Toxins on Human Serum Albumin.
Sakai, T., Takadate, A., & OTAGIRI, M. (1995) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.18.1755 · Cited by 134 · see citing works
Self-citationKragh‐Hansen, U. (1988) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09363-0 · Cited by 130 · see citing works
The free fatty acids bound to human serum albumin
Saifer, A., & Goldman, L. (1961) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39014-3 · Cited by 122 · see citing works
Relations between high-affinity binding sites of markers for binding regions on human serum albumin
Kragh‐Hansen, U. (1985) · Biochemical Journal · doi:10.1042/bj2250629 · Cited by 116 · see citing works
Effects of Fatty Acids on Two Specific Drug Binding Sites on Human Serum Albumin
Birkett, D., Myers, S., & Sudlow, G. (1977) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)12512-1 · Cited by 98 · see citing works
Vorum, H., & Honoré, B. (1996) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.1996.tb03990.x · Cited by 93 · see citing works
Cistola, D. P., & SMALL, D. M. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115149 · Cited by 91 · see citing works
Kleywegt, G. J., Henrick, K., Dodson, E. J., et al. (2003) · Structure · doi:10.1016/s0969-2126(03)00186-2 · Cited by 88 · see citing works
Rational Design of Diflunisal Analogues with Reduced Affinity for Human Serum Albumin
Mao, H., Hajduk, P. J., Craig, R., Bell, R., Borre, T., & Fesik, S. W. (2001) · Journal of the American Chemical Society · doi:10.1021/ja015955b · Cited by 87 · see citing works
Quantitative analysis of allosteric drug-protein binding by biointeraction chromatography
Chen, J., & Hage, D. S. (2004) · Nature Biotechnology · doi:10.1038/nbt1022 · Cited by 76 · see citing works
Sakai, T., Yamasaki, K., Sako, T., Kragh‐Hansen, U., Suenaga, A., & Otagiri, M. (2001) · Pharmaceutical Research · doi:10.1023/a:1011014629551 · Cited by 75 · see citing works
Self-citationSaiakhov, R., Stefan, L. R., & Klopman, G. (2000) · Perspectives in Drug Discovery and Design · doi:10.1023/a:1008723723679 · Cited by 67 · see citing works
Schumacher, M. A., & Brennan, R. G. (2003) · Research in Microbiology · doi:10.1016/s0923-2508(02)00013-x · Cited by 51 · see citing works
Ligand binding to domain-3 of human serum albumin: a chemometric analysis
Hajduk, P. J., Mendoza, R. R., Petros, A. M., Huth, J. R., Bures, M. G., Fesik, S. W., & Martin, Y. C. (2003) · Journal of Computer-Aided Molecular Design · doi:10.1023/a:1025305520585 · Cited by 50 · see citing works
Tsutsumi, Y., Maruyama, T., Takadate, A., et al. (1999) · Pharmaceutical Research · doi:10.1023/a:1018842506896 · Cited by 46 · see citing works
Fitos, I., Visy, J., Simonyi, M., et al. (1999) · Chirality · doi:10.1002/(sici)1520-636x(1999)11:2 · Cited by 42 · see citing works
Henderson, S. J., & LINDUP, W. E. (1990) · Biochemical Pharmacology · doi:10.1016/0006-2952(90)90097-5 · Cited by 34 · see citing works
Buchholz, L., Cai, C., Andress, L. D., et al. (2002) · European Journal of Pharmaceutical Sciences · doi:10.1016/s0928-0987(01)00219-6 · Cited by 32 · see citing works
Baltsen, M., & Byskov, A. G. (1999) · Biomedical Chromatography · doi:10.1002/(sici)1099-0801(199910)13:6 · Cited by 29 · see citing works
Displacement of Bilirubin from Adult and Newborn Serum Albumin by a Drug and Fatty Acid
Ivarsen, P., & Brodersen, R. (2019) · Developmental Pharmacology and Therapeutics · doi:10.1159/000480978 · Cited by 18 · see citing works
Dort, M. E. V. (1999) · Chirality · doi:10.1002/(sici)1520-636x(1999)11:9 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Hypoalbuminemia: Pathogenesis and Clinical Significance
Soeters, P. B., Wolfe, R. R., & Shenkin, A. (2019) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.1451 · Cited by 1,448 · see citing works
The antioxidant properties of serum albumin
Roche, M., Rondeau, P., Singh, N. R., Tarnus, E., & Bourdon, E. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.04.057 · Cited by 1,255 · see citing works
Interactive Association of Drugs Binding to Human Serum Albumin
Yang, F., Zhang, Y., & Liang, H. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15033580 · Cited by 376 · see citing works
Hemoglobin and heme scavenging
Ascenzi, P., Bocedi, A., Visca, P., Altruda, F., Tolosano, E., Beringhelli, T., & Fasano, M. (2005) · IUBMB Life (International Union of Biochemistry and Molecular Biology: Life) · doi:10.1080/15216540500380871 · Cited by 280 · see citing works
Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders
Smith, A., & McCulloh, R. J. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00187 · Cited by 258 · see citing works
Allendorf, F., Berger, U., Goss, K.-U., & Ulrich, N. (2019) · Environmental Science: Processes & Impacts · doi:10.1039/c9em00290a · Cited by 74 · see citing works
Laskaris, P., Atrouni, A., Calera, J. A., d'Enfert, C., Munier-Lehmann, H., Cavaillon, J.-M., Latgé, J.-P., & Ibrahim-Granet, O. (2016) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00324-16 · Cited by 37 · see citing works
Myatt, D. P. (2017) · Biomedical Spectroscopy and Imaging · doi:10.3233/bsi-170165 · Cited by 10 · see citing works
- Authors
- Ghuman, J., Zunszain, P. A., Petitpas, I., Bhattacharya, A. A., Otagiri, M., & Curry, S.
- Affiliations
- Imperial College London (GB)
- Kumamoto University (JP)
- Corresponding author
- Curry, Stephen
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2005-10
- Volume
- 353
- Issue
- 1
- Pages
- 38-52
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2016401253
- Cited by
- 1,941
- References
- 56
- Citations by year
- 2026: 86 · 2025: 94 · 2024: 117 · 2023: 135 · 2022: 122 · 2021: 112 · 2020: 105 · 2019: 118 · 2018: 113 · 2017: 128 · 2016: 130 · 2015: 110 · 2014: 99 · 2013: 99 · 2012: 74
- FWCI
- 14.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Deutsches Elektronen-Synchrotron
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- human serum albumin, drug binding, binding specificity, protein-ligand complex, crystal structure, drug binding sites, fatty acid binding, binding site flexibility, drug development, binding affinity
- MeSH terms
- Binding Sites, Pharmaceutical Preparations, Humans, Ligands, Models, Molecular, Protein Binding, Serum Albumin, Structure-Activity Relationship, Substrate Specificity, Protein Structure, Tertiary, Crystallography, X-Ray, Myristic Acid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review