A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance.

ABSTRACT: Mutations of the androgen receptor (AR) associated with prostate cancer and androgen insensitivity syndrome may profoundly influence its structure, protein interaction network, and binding to chromatin, resulting in altered transcription signatures and drug responses. Current structural information fails to explain the effect of pathological mutations on AR structure-function relationship. Here, we have thoroughly studied the effects of selected mutations that span the complete dimer interface of AR ligand-binding domain (AR-LBD) using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that incre

SUBMITTER: Alegre-Marti A 

PROVIDER: S-EPMC10017050 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature