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Cited by 91Estrogen and related hormone effectsProtein Interaction Studies and Fluorescence AnalysisProtein Structure and Dynamics

Structural analyses of sex hormone-binding globulin reveal novel ligands and function

Avvakumov, George V., Cherkasov, Artem, Muller, Yves A., Hammond, Geoffrey L.·2010·Molecular and Cellular Endocrinology
DOI 10.1016/j.mce.2009.09.005
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Abstract

Plasma sex hormone-binding globulin (SHBG) regulates the access of androgens and estrogens to their target tissues and cell types. An SHBG homologue, known as the androgen-binding protein, is expressed in Sertoli cells of many mammalians, but testicular expression of human SHBG is restricted to germ cells. The primary structure of SHBG comprises tandem laminin G-like (LG) domains. The amino-terminal LG-domain includes the steroid-binding site and dimerization interface, and its tertiary structure, resolved in complex with natural and synthetic sex steroids, has revealed unanticipated mechanisms of steroid binding at the atomic level. This LG-domain interacts with fibulin-1D and fibulin-2 in a ligand-specific manner, and this is attributed to the unique way estrogens reside within the steroid-binding site, and the ordering of an otherwise flexible loop structure covering the entrance of the steroid-binding pocket. This mechanism enables estradiol to enhance the sequestration of plasma SHBG by the stroma of some tissues through binding to these extra-cellular matrix-associated proteins. The human SHBG amino-terminal LG-domain also contains several cation-binding sites, and occupancy of a zinc-binding site influences its affinity for estradiol. The complete quaternary structure of SHBG remains unresolved but structural predictions suggest that the carboxy-terminal LG-domains extend laterally from the dimerized amino-terminal LG-domains. The carboxy-terminal LG-domain contains two N-glycosylation sites, but their biological significance remains obscure. Knowledge of the SHBG tertiary structure has helped develop computational techniques based on the use of a "bench-mark data set" of steroid ligands, and created novel drug discovery and toxicology risk assessment platforms.

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  • SHBG binds sex steroids (including active androgens, oestrogens, precursors and metabolites) with high specificity and affinity (nanomolar ranges).

    “In contrast, SHBG binds sex steroids (including active androgens, oestrogens, precursors and metabolites (Avvakumov et al., 2010, Cherkasov et al., 2008, Dunn et al., 1981, Grishkovskaya et al., 2002)) with high specificity and affinity (nanomolar ranges) (reviewed in (Hammond, 2016)).”

    From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Avvakumov et al., 2010

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Authors
Avvakumov, G. V., Cherkasov, A., Muller, Y. A., & Hammond, G. L.
Affiliations
  • University of Toronto (CA)
  • University of British Columbia (CA)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
Corresponding author
Hammond, Geoffrey L.
ORCID
Venue
Molecular and Cellular Endocrinology
Publisher
Elsevier BV
Published
2010-03
Volume
316
Issue
1
Pages
13-23
ISSN
0303-7207 (ISSN-L)
DOI
10.1016/j.mce.2009.09.005
OpenAlex
W2063736854
Cited by
91
References
67
Citations by year
2026: 4 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 1 · 2021: 8 · 2020: 5 · 2019: 9 · 2018: 7 · 2017: 6 · 2016: 8 · 2015: 4 · 2014: 7 · 2013: 3 · 2012: 6
FWCI
0.38
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Molecular and Cellular Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Canadian Institutes of Health Research (MOP 15261)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • 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
Keywords
sex hormone-binding globulin, steroid binding sites, estradiol binding, fibulin-2, extracellular matrix, zinc binding site, cation binding sites, quaternary structure, N-glycosylation, androgen-binding protein, Sertoli cells, drug discovery
MeSH terms
Animals, Binding Sites, Carbohydrates, Computer Simulation, Humans, Ligands, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Conformation, Sex Hormone-Binding Globulin, Zinc, Crystallography, X-Ray

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