title: Systems Structural Biology Analysis of Ligand Effects on ERα Predicts Cellular Response to Environmental Estrogens and Anti-hormone Therapies.
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.
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Nwachukwu
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Sathish
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Nelson E
authors.initials: NE
authors.lastname: Bruno
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Nowak
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wright
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Erumbi S
authors.initials: ES
authors.lastname: Rangarajan
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Izard
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Xin-Qui
authors.initials: XQ
authors.lastname: Yao
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Grant
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kojetin
authors.affiliation: Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA. Electronic address: knettles@scripps.edu.
authors.forename: Kendall W
authors.initials: KW
authors.lastname: Nettles
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands
keywords: X-ray crystallography; allosteric signaling; breast cancer; endocrine disruptor; estrogen receptor-α; nuclear receptor; steroid hormone