Coupling of receptor conformation and ligand orientation determine graded activity
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Small molecules stabilize specific protein conformations from a larger ensemble, enabling molecular switches that control diverse cellular functions. We show here that the converse also holds true: the conformational state of the estrogen receptor can direct distinct orientations of the bound ligand. 'Gain-of-allostery' mutations that mimic the effects of ligand in driving protein conformation allowed crystallization of the partial agonist ligand WAY-169916 with both the canonical active and inactive conformations of the estrogen receptor. The intermediate transcriptional activity induced by WAY-169916 is associated with the ligand binding differently to the active and inactive conformations of the receptor. Analyses of a series of chemical derivatives demonstrated that altering the ensemble of ligand binding orientations changes signaling output. The coupling of different ligand binding orientations to distinct active and inactive protein conformations defines a new mechanism for titrating allosteric signaling activity.
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Comparing classes of structures allowed identification of common features across many structures and space groups and statistical characterization of subtle features within single-structure noise.
“Comparison of classes of structures enabled identification of common features across many structures and space groups, and allowed statistical analysis and characterization of subtle features within the noise of a single structure, as we previously used for dissecting estrogen receptor signaling (Bruning et al., 2010; Nettles et al., 2004, 2008).”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Bruning et al., 2010
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- Authors
- Bruning, J. B., Parent, A. A., Gil, G., Zhao, M., Nowak, J., Pace, M. C., Smith, C. L., Afonine, P. V., Adams, P. D., Katzenellenbogen, J. A., & Nettles, K. W.
- Affiliations
- Scripps Research Institute (US)
- University of Illinois Urbana-Champaign (US)
- Baylor College of Medicine (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Nettles, Kendall W
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2010-10-10
- Volume
- 6
- Issue
- 11
- Pages
- 837-843
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC2974172
- OpenAlex
- W1976738153
- Cited by
- 142
- References
- 48
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 9 · 2023: 7 · 2022: 7 · 2021: 12 · 2020: 3 · 2019: 12 · 2018: 7 · 2017: 10 · 2016: 10 · 2015: 8 · 2014: 18 · 2013: 8 · 2012: 10
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- National Cancer Institute (R33CA132022, CA132022)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK015556, DK077085, R37DK15556, R01DK077085, R01DK053002, DK53002)
- National Institute of Neurological Disorders and Stroke (R21NS056998)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- estrogen receptor, ligand-binding domain, partial agonists, protein conformation, ligand binding orientation, allosteric communication
- MeSH terms
- Allosteric Regulation, Binding Sites, Breast Neoplasms, Dose-Response Relationship, Drug, Humans, Ligands, Mutation, Protein Conformation, Pyrazoles, Receptors, Estrogen, Time Factors, Signal Transduction, Reverse Transcriptase Polymerase Chain Reaction, Cell Line, Tumor
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