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Structural insights into selective agonist actions of tamoxifen on human estrogen receptor alpha

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Abstract

Tamoxifen—an anti-estrogenic ligand in breast tissues used as a first-line treatment in estrogen receptor (ER)-positive breast cancers—is associated with the development of resistance followed by resumption of tumor growth in about 30 % of cases. Whether tamoxifen assists in proliferation in such cases or whether any ligand-independent pathway to transcription exists is not fully understood; also, no ERα mutants have been detected so far that could lead to tamoxifen resistance. Using in silico conformational analysis of the ERα ligand binding domain (LBD), in the absence and presence of selective agonist (diethylstilbestrol; DES), antagonist (Faslodex; ICI), and selective estrogen receptor modulator (SERM; 4-hydroxy tamoxifen; 4-OHT) ligands, we have elucidated ligand-responsive structural modulations of the ERα-LBD dimer in its agonist and antagonist complexes to address the issue of “tamoxifen resistance”. DES and ICI were found to stabilize the dimer in their agonist and antagonist conformations, respectively. The ERα-LBD dimer without the presence of any bound ligand also led to a stable structure in agonist conformation. However, binding of 4-OHT to the antagonist structure led to a flexible conformation allowing the protein to visit conformations populated by agonists as was evident from principal component analysis and radius of gyration plots. Further, the relaxed conformations of the 4-OHT bound protein exhibited a diminished size of the co-repressor binding pocket in the LBD, thus signaling a partial blockage of the co-repressor binding motif. Thus, the ability of 4-OHT-bound ERα-LBD to assume flexible conformations visited by agonists and reduced co-repressor binding surface at the LBD provide crucial structural insights into tamoxifen-resistance that complement our existing understanding.

4-OHT bound ERα dimer visits both antagonist and agonist conformational subspaces. The Co-repressor binding site reduces significantly in 4-OHT bound agonist conformation.

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Acknowledgments

The authors acknowledge financial support from Mississippi IDeA Networks of Biomedical Research Excellence (MS-INBRE) funded by National Center for Research Resources/National Institutes of Health (NCRR/NIH; 5P20RR016476-11) and National Institute of General Medical Sciences (NIGMS/NIH; 8 P20 GM103476-11). P.K.B. acknowledges additional support from Experimental Program to Stimulate Competitive Research (EPSCoR) (EPS-0903787; Sub-contract: 190200-362492-10).

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Authors and Affiliations

  1. Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174, USA

    Sandipan Chakraborty & Pradip Kumar Biswas

  2. Saroj Mohan Institute of Technology, Guptipara, Hooghly, 712512, West Bengal, India

    Sandipan Chakraborty

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  1. Sandipan Chakraborty
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Correspondence to Pradip Kumar Biswas.

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Chakraborty, S., Biswas, P.K. Structural insights into selective agonist actions of tamoxifen on human estrogen receptor alpha. J Mol Model 20, 2338 (2014). https://doi.org/10.1007/s00894-014-2338-x

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