5KRF

Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in Complex with the Dynamic WAY derivative, 1a

Summary for 5KRF

• Entry DOI: 10.2210/pdb5krf/pdb
• Descriptor: Estrogen receptor, KHKILHRLLQDSSS Peptide, 4-[1-methyl-7-(trifluoromethyl)indazol-3-yl]benzene-1,3-diol, ... (4 entities in total)
• Functional Keywords: nuclear receptor, transcription factor, ligand binding, protein-ligand complex, transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Isoform 1: Nucleus . Isoform 3: Nucleus. Nucleus: P03372
• Total number of polymer chains: 4
• Total formula weight: 62549.47

Authors

Nwachukwu, J.C.,Srinivasan, S.,Bruno, N.E.,Nowak, J.,Kojetin, D.J.,Elemento, O.,Katzenellenbogen, J.A.,Nettles, K.W. (deposition date: 2016-07-07, release date: 2017-02-15, Last modification date: 2024-03-06)

Primary citation

Nwachukwu, J.C.,Srinivasan, S.,Bruno, N.E.,Nowak, J.,Wright, N.J.,Minutolo, F.,Rangarajan, E.S.,Izard, T.,Yao, X.Q.,Grant, B.J.,Kojetin, D.J.,Elemento, O.,Katzenellenbogen, J.A.,Nettles, K.W.
Systems Structural Biology Analysis of Ligand Effects on ER alpha Predicts Cellular Response to Environmental Estrogens and Anti-hormone Therapies.
Cell Chem Biol, 24:35-45, 2017

PubMed 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.

PubMed: 28042045
DOI: 10.1016/j.chembiol.2016.11.014

Experimental method

X-RAY DIFFRACTION (2.193 Å)