Cited by 1,941Protein Interaction Studies and Fluorescence AnalysisProtein Structure and DynamicsComputational Drug Discovery Methods

Structural Basis of the Drug-binding Specificity of Human Serum Albumin

Ghuman, Jamie, Zunszain, Patricia A., Petitpas, Isabelle, Bhattacharya, Ananyo A., Otagiri, Masaki, Curry, Stephen·2005·Journal of Molecular Biology

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.

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Registry

Crossref · 10.1016/j.jmb.2005.07.075

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  • 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]

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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

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