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Updated: Jul 11, 2026
09:07
Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
Published on: December 19, 2018
A surface on the androgen receptor that allosterically regulates coactivator binding
Eva Estébanez-Perpiñá1, Leggy A Arnold, Alexander A Arnold
1Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.
Summary
Researchers identified a new way to inhibit the androgen receptor (AR) by targeting a surface cleft called binding function (BF)-3. This approach may overcome resistance to current prostate cancer treatments.
Area of Science:
- Molecular Biology
- Structural Biology
- Medicinal Chemistry
Background:
- Current nuclear receptor (NR) inhibitors target the hormone binding pocket, facing limitations.
- Androgen receptor (AR) is crucial in prostate cancer, but resistance to anti-androgen therapies develops.
- Novel strategies are needed to overcome limitations of existing AR inhibitors.
Purpose of the Study:
- To identify compounds that bind the AR surface and inhibit coactivator binding.
- To explore alternative inhibition strategies beyond the hormone binding pocket.
- To investigate a previously unrecognized regulatory site on the AR.
Main Methods:
- Functional and X-ray screens were employed to identify AR surface-binding compounds.
- Coactivator binding inhibition was assessed in solution and cellular assays.
- X-ray crystallography was used to visualize compound binding and structural effects.
Main Results:
- Four compounds, including NSAIDs and 3,3',5-triiodothyroacetic acid, inhibited coactivator binding (IC50 ~50 microM) and AR AF-2 activity.
- The most potent inhibitors preferentially bound a novel surface cleft, binding function (BF)-3.
- 3,3',5-triiodothyroacetic acid binding to BF-3 remodeled the adjacent AF-2 site, weakening coactivator interaction.
Conclusions:
- Binding function (BF)-3 is a previously unrecognized allosteric regulatory site on the AR.
- BF-3 is essential for AR activity in vivo and a potential pharmaceutical target.
- Targeting BF-3 offers a promising strategy to overcome anti-androgen resistance in prostate cancer.
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