Novel Selective Inhibitors of the Interaction of Individual Nuclear Hormone Receptors with a Mutually Shared Steroid Receptor Coactivator 2
Abstract
Nuclear hormone receptor (NR) signaling, currently a therapeutic target in multiple diseases, involves an ordered series of protein interactions to regulate transcription in response to changing hormone levels. Later steps in the process of ligand-dependent signaling are driven by a highly conserved interaction between the NRs and the steroid receptor coactivators (SRCs) that is effected by a conserved interaction motif (L1XXL2L3), known as an NR box. Using computational design and combinatorial chemistry, we have produced novel alpha-helical proteomimetics of the second NR box of SRC2 that exploit structural differences between human estrogen receptor alpha (hERalpha), human estrogen receptor beta (hERbeta), and human thyroid hormone receptor beta (hTRbeta). The resulting library sequentially replaced each leucine with non-natural side chains. Screening this library using a quantitative competition assay revealed compounds that selectively inhibit the interaction of SRC2-2 with each individual NR in preference to its interaction with the other NR. This approach generated highly selective compounds from one that had no specificity for a particular family member. These compounds represent the first family-member-selective competitive inhibitors of the protein interactions of transcription factors.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Cites
Combinatorial Control of Gene Expression by Nuclear Receptors and Coregulators
McKenna, N. J., & O'Malley, B. W. (2002) · Cell · doi:10.1016/s0092-8674(02)00641-4 · Cited by 1,463 · see citing works
Structure and specificity of nuclear receptor–coactivator interactionsPreprint
Darimont, B. D., Wagner, R. L., Apriletti, J. W., Stallcup, M. R., Kushner, P. J., Baxter, J. D., Fletterick, R. J., & Yamamoto, K. R. (1998) · Genes & Development · doi:10.1101/gad.12.21.3343 · Cited by 921 · see citing works
Hormone-Dependent Coactivator Binding to a Hydrophobic Cleft on Nuclear Receptors
Feng, W., Ribeiro, R. C. J., Wagner, R. L., Nguyen, H. T., Apriletti, J. W., Fletterick, R. J., Baxter, J. D., Kushner, P. J., & West, B. L. (1998) · Science · doi:10.1126/science.280.5370.1747 · Cited by 579 · see citing works
Geistlinger, T., & Guy, R. K. (2001) · Journal of the American Chemical Society · doi:10.1021/ja005549c · Cited by 39 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Inhibition of α-helix-mediated protein–protein interactions using designed molecules
Azzarito, V., Long, K., Murphy, N. S., & Wilson, A. J. (2013) · Nature Chemistry · doi:10.1038/nchem.1568 · Cited by 727 · see citing works
Modulators of Protein–Protein Interactions
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L., & Ottmann, C. (2014) · Chemical Reviews · doi:10.1021/cr400698c · Cited by 497 · see citing works
Development of α-Helical Calpain Probes by Mimicking a Natural Protein–Protein Interaction
Jo, H., Meinhardt, N., Wu, Y., Kulkarni, S., Hu, X., Low, K. E., Davies, P. L., DeGrado, W. F., & Greenbaum, D. C. (2012) · Journal of the American Chemical Society · doi:10.1021/ja307599z · Cited by 261 · see citing works
Design and Structure of Stapled Peptides Binding to Estrogen Receptors
Phillips, C., Roberts, L. R., Schade, M., Bazin, R., Bent, A., Davies, N. L., Moore, R., Pannifer, A. D., Pickford, A. R., Prior, S. H., et al. (2011) · Journal of the American Chemical Society · doi:10.1021/ja202946k · Cited by 247 · see citing works
Galande, A. K., Bramlett, K. S., Burris, T. P., Wittliff, J. L., & Spatola, A. F. (2004) · The Journal of Peptide Research · doi:10.1111/j.1399-3011.2004.00152.x · Cited by 69 · see citing works
Proline primed helix length as a modulator of the nuclear receptor-coactivator interaction
Fuchs, S., Nguyen, H. D., Phan, T. T. P., Burton, M. F., Nieto, L., de Vries-van Leeuwen, I. J., Schmidt, A., Goodarzifard, M., Agten, S. M., Rose, R., et al. (2013) · Journal of the American Chemical Society · doi:10.1021/ja311748r · Cited by 43 · see citing works
A “cross-stitched” peptide with improved helicity and proteolytic stability
Speltz, T. E., Mayne, C. G., Fanning, S. W., Siddiqui, Z., Tajkhorshid, E., Greene, G. L., & Moore, T. W. (2018) · Organic & Biomolecular Chemistry · doi:10.1039/c8ob00790j · Cited by 39 · see citing works
- Authors
- Geistlinger, T. R., & Guy, R. K.
- Affiliations
- Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California at San Francisco, Genentech Hall, Mission Bay, 600 16th Street 2280, San Francisco, California 94143-2280
- University of California, San Francisco (US)
- ORCID
- Guy, R. Kiplin
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2003-05-16
- Volume
- 125
- Issue
- 23
- Pages
- 6852-6853
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2037743832
- Cited by
- 94
- References
- 4
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 2 · 2020: 2 · 2019: 5 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 8 · 2014: 8 · 2013: 2 · 2012: 8
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058080, R01 DK58080)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- nuclear receptors, SRC-2, protein-protein interaction inhibitors, estrogen receptor alpha, estrogen receptor beta, thyroid hormone receptor beta, combinatorial chemistry, competitive binding assay, transcriptional coactivator, ligand-dependent signaling
- MeSH terms
- Peptides, Receptors, Estrogen, Receptors, Thyroid Hormone, Transcription Factors, Thyroid Hormone Receptors beta, Biomimetic Materials, Estrogen Receptor alpha, Nuclear Receptor Coactivator 2
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
