Ligand dissociation from estrogen receptor is mediated by receptor dimerization: evidence from molecular dynamics simulations.

Molecular Endocrinology
Milton T SonodaI Polikarpov

Abstract

Estrogen Receptor (ER) is an important target for pharmaceutical design. Like other ligand-dependent transcription factors, hormone binding regulates ER transcriptional activity. Nevertheless, the mechanisms by which ligands enter and leave ERs and other nuclear receptors remain poorly understood. Here, we report results of locally enhanced sampling molecular dynamics simulations to identify dissociation pathways of two ER ligands [the natural hormone 17beta-estradiol (E(2)) and the selective ER modulator raloxifene (RAL)] from the human ERalpha ligand-binding domain in monomeric and dimeric forms. E(2) dissociation occurs via three different pathways in ER monomers. One resembles the mousetrap mechanism (Path I), involving repositioning of helix 12 (H12), others involve the separation of H8 and H11 (Path II), and a variant of this pathway at the bottom of the ligand-binding domain (Path II'). RAL leaves the receptor through Path I and a Path I variant in which the ligand leaves the receptor through the loop region between H11 and H12 (Path I'). Remarkably, ER dimerization strongly suppresses Paths II and II' for E(2) dissociation and modifies RAL escape routes. We propose that differences in ligand release pathways detected in...Continue Reading

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Citations

Oct 7, 2008·European Biophysics Journal : EBJ·Mikael Peräkylä
Apr 8, 2010·Pharmaceutical Research·Subhajit Mukherjee, Sridhar Mani
Jun 1, 2010·European Biophysics Journal : EBJ·Alexandre Suman de AraujoIgor Polikarpov
Dec 2, 2014·Trends in Biochemical Sciences·Fraydoon RastinejadIgor Polikarpov
Sep 5, 2009·The Journal of Steroid Biochemistry and Molecular Biology·Suzana T Cunha LimaPaul Webb
May 12, 2009·Drug Discovery Today·Ni AiSean Ekins
Apr 1, 2016·Scientific Reports·Srinivasaraghavan KannanChandra S Verma
Feb 15, 2018·The Journal of Endocrinology·Cyril S Anyetei-AnumLizabeth A Allison
Feb 21, 2014·Molecular Endocrinology·P C T SouzaI Polikarpov
Jul 13, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Alexander Eisold, Dirk Labudde
Jul 9, 2009·The Journal of Physical Chemistry. B·Jie ShenHualiang Jiang
Jan 2, 2010·The Journal of Physical Chemistry. B·Leandro MartínezMunir S Skaf
Oct 30, 2012·Journal of Chemical Information and Modeling·Weihua LiYun Tang
Jun 28, 2019·Journal of Chemical Information and Modeling·André Fischer, Martin Smieško

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