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Cell Chem Biol. 2017 Jan 19;24(1):35-45. doi: 10.1016/j.chembiol.2016.11.014. Epub 2016 Dec 29.

Systems Structural Biology Analysis of Ligand Effects on ERα Predicts Cellular Response to Environmental Estrogens and Anti-hormone Therapies.

Author information

1
Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
2
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
3
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
4
Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
5
Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA.
6
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, IL 61801, USA.
7
Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA. Electronic address: knettles@scripps.edu.

Abstract

Environmental estrogens and anti-hormone therapies for breast cancer have diverse tissue- and signaling-pathway-selective outcomes, but how estrogen receptor alpha (ERα) mediates this phenotypic diversity is poorly understood. We implemented a statistical approach to allow unbiased, parallel analyses of multiple crystal structures, and identified subtle perturbations of ERα structure by different synthetic and environmental estrogens. Many of these perturbations were in the sub-Å range, within the noise of the individual structures, but contributed significantly to the activities of synthetic and environmental estrogens. Combining structural perturbation data from many structures with quantitative cellular activity profiles of the ligands enabled identification of structural rules for ligand-specific allosteric signaling-predicting activity from structure. This approach provides a framework for understanding the diverse effects of environmental estrogens and for guiding iterative medicinal chemistry efforts to generate improved breast cancer therapies, an approach that can be applied to understanding other ligand-regulated allosteric signaling pathways.

KEYWORDS:

X-ray crystallography; allosteric signaling; breast cancer; endocrine disruptor; estrogen receptor-α; nuclear receptor; steroid hormone

PMID:
28042045
DOI:
10.1016/j.chembiol.2016.11.014
[Indexed for MEDLINE]
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