Defining the Energetic Basis for a Conformational Switch Mediating Ligand-Independent Activation of Mutant Estrogen Receptors in Breast Cancer.

ABSTRACT: Although most primary estrogen receptor (ER)-positive breast cancers respond well to endocrine therapies, many relapse later as metastatic disease due to endocrine therapy resistance. Over one third of these are associated with mutations in the ligand-binding domain (LBD) that activate the receptor independent of ligand. We have used an array of advanced computational techniques rooted in molecular dynamics simulations, in concert with and validated by experiments, to characterize the molecular mechanisms by which specific acquired somatic point mutations give rise to ER constitutive activation. By comparing structural and energetic features of constitutively active mutants and ligand-bound forms of ER-LBD with unliganded wild-type (WT) ER, we characterize a spring force originating from s

SUBMITTER: Mayne CG 

PROVIDER: S-EPMC8419021 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature