A surface on the androgen receptor that allosterically regulates coactivator binding
Open accessAbstract
Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.
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Binding at the AR BF3 surface allosterically affects AF2 conformation.
“Given that binding at the AR BF3 surface is known to allosterically affect AF2 conformation [24], FKBP52 interaction with β-catenin to regulate AR through the BF3 surface could indirectly affect co-activator binding at AF2.”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [24]
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“In addition, mammalian two-hybrid studies suggested that β-catenin interacts with AR activation function 2 (AF2) [18], a site that is affected allosterically by small molecule binding at the AR BF3 surface [24].”
BackgroundSelf-citation
- Authors
- Estébanez-Perpiñá, E., Arnold, L. A., Nguyen, P., Rodrigues, E. D., Mar, E., Bateman, R., Pallai, P., Shokat, K. M., Baxter, J. D., Guy, R. K., Webb, P., & Fletterick, R. J.
- Affiliations
- *Department of Biochemistry and Biophysics,
- St. Jude Children's Research Hospital (US)
- University of California, San Francisco (US)
- Department of Molecular and Cellular Pharmacology, and
- Bioblocks, Inc., San Diego, CA 92121
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-10-09
- Volume
- 104
- Issue
- 41
- Pages
- 16074-16079
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1999396
- OpenAlex
- W2127226545
- Cited by
- 307
- References
- 41
- Citations by year
- 2026: 4 · 2025: 17 · 2024: 15 · 2023: 18 · 2022: 21 · 2021: 14 · 2020: 13 · 2019: 10 · 2018: 13 · 2017: 18 · 2016: 16 · 2015: 21 · 2014: 30 · 2013: 20 · 2012: 21
- FWCI
- 11.28
- Type
- journal article
- Language
- en
- Update notices
- correction (2007-11-20)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W81XWH)
- Prostate Cancer Foundation
- National Institutes of Health (W81XWH, DK41482, DK51281)
- University of California, San Francisco
- National Cancer Institute (CA 89520, P50CA089520)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 41482, DK51281, R55DK058080, R01DK058080, R01DK051281, DK58080)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- androgen receptor, allosteric regulation, coactivator binding, AF-2, antiandrogen resistance, prostate cancer, nonsteroidal anti-inflammatory drugs, triiodothyroacetic acid, X-ray crystal structure, androgen insensitivity syndrome, drug target identification
- MeSH terms
- Allosteric Site, Animals, Models, Molecular, Receptors, Androgen, Recombinant Proteins, Protein Structure, Tertiary, Crystallography, X-Ray, Mice, Nuclear Receptor Coactivator 2, Androgen Receptor Antagonists, In Vitro Techniques
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