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

Nwachukwu JC, Srinivasan S, Bruno NE, Nowak J, Wright NJ, Minutolo F, Rangarajan ES, Izard T, Yao XQ, Grant BJ, Kojetin DJ, Elemento O, Katzenellenbogen JA, Nettles KW
Cell Chem Biol 24 35-45 (2017)

Cited: 13 times
EuropePMC logo PMID: 28042045

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.

Reviews citing this publication (3)

  1. Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance. Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, Greene GL, Chandarlapaty S. Nat Rev Cancer 18 377-388 (2018)
  2. Toxicodynamics of Mycotoxins in the Framework of Food Risk Assessment-An In Silico Perspective. Dellafiora L, Dall'Asta C, Galaverna G. Toxins (Basel) 10 E52 (2018)
  3. Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens. Mazurek AH, Szeleszczuk Ł, Simonson T, Pisklak DM. Int J Mol Sci 21 E6411 (2020)

Articles citing this publication (10)

  1. Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells. Stender JD, Nwachukwu JC, Kastrati I, Kim Y, Strid T, Yakir M, Srinivasan S, Nowak J, Izard T, Rangarajan ES, Carlson KE, Katzenellenbogen JA, Yao XQ, Grant BJ, Leong HS, Lin CY, Frasor J, Nettles KW, Glass CK. Mol Cell 65 1122-1135.e5 (2017)
  2. Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study. Aichinger G, Dellafiora L, Pantazi F, Del Favero G, Galaverna G, Dall'Asta C, Marko D. Arch Toxicol 94 2225-2237 (2020)
  3. Comparison of Data Fusion Methods as Consensus Scores for Ensemble Docking. Bajusz D, Rácz A, Héberger K. Molecules 24 E2690 (2019)
  4. Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling. Bruno NE, Nwachukwu JC, Srinivasan S, Nettles CC, Izard T, Jin Z, Nowak J, Cameron MD, Boregowda SV, Phinney DG, Elemento O, Liu X, Ortlund EA, Houtman R, Stavreva DA, Hager GL, Kamenecka TM, Kojetin DJ, Nettles KW. Nat Chem Biol 17 307-316 (2021)
  5. Human Estrogen Receptor Alpha Antagonists, Part 3: 3-D Pharmacophore and 3-D QSAR Guided Brefeldin A Hit-to-Lead Optimization toward New Breast Cancer Suppressants. Kurtanović N, Tomašević N, Matić S, Proia E, Sabatino M, Antonini L, Mladenović M, Ragno R. Molecules 27 2823 (2022)
  6. Quality Control for Single Cell Imaging Analytics Using Endocrine Disruptor-Induced Changes in Estrogen Receptor Expression. Stossi F, Singh PK, Mistry RM, Johnson HL, Dandekar RD, Mancini MG, Szafran AT, Rao AU, Mancini MA. Environ Health Perspect 130 27008 (2022)
  7. Radioiodination of zearalenone and determination of Lactobacillus plantarum effect of on zearalenone organ distribution: In silico study and preclinical evaluation. Sanad MH, Farag AB, Bassem SA, Marzook FA. Toxicol Rep 9 470-479 (2022)
  8. Comparative Study on the Sensing Kinetics of Carbon and Nitrogen Nutrients in Cancer Tissues and Normal Tissues Based Electrochemical Biosensors. Lu D, Liu D, Liu Y, Wang X, Liu Y, Yuan S, Ren R, Pang G. Molecules 28 1453 (2023)
  9. Network pharmacology of apigeniflavan: a novel bioactive compound of Trema orientalis Linn. in the treatment of pancreatic cancer through bioinformatics approaches. Das R, Agrawal S, Kumar P, Singh AK, Shukla PK, Bhattacharya I, Tiwari KN, Mishra SK, Tripathi AK. 3 Biotech 13 160 (2023)
  10. ER/AR Multi-Conformational Docking Server: A Tool for Discovering and Studying Estrogen and Androgen Receptor Modulators. Wang F, Hu S, Ma DQ, Li Q, Li HC, Liang JY, Chang S, Kong R. Front Pharmacol 13 800885 (2022)


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