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

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

SUBMITTER: Sonoda MT 

PROVIDER: S-EPMC5419439 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature