7ZTZ

Crystal structure of mutant AR-LBD (Y764C) bound to dihydrotestosterone

7ZTZ の概要

• エントリーDOI: 10.2210/pdb7ztz/pdb
• 関連するPDBエントリー: 7ZTV 7ZTX
• 分子名称: Androgen receptor, 5-ALPHA-DIHYDROTESTOSTERONE, IMIDAZOLE, ... (5 entities in total)
• 機能のキーワード: hormone receptor, nuclear receptor, dht receptor, dna binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29441.63

構造登録者

Alegre-Marti, A.,Jimenez-Panizo, A.,Estebanez-Perpina, E.,Fuentes-Prior, P. (登録日: 2022-05-11, 公開日: 2023-03-22, 最終更新日: 2024-02-07)

主引用文献

Alegre-Marti, A.,Jimenez-Panizo, A.,Martinez-Tebar, A.,Poulard, C.,Peralta-Moreno, M.N.,Abella, M.,Anton, R.,Chinas, M.,Eckhard, U.,Piulats, J.M.,Rojas, A.M.,Fernandez-Recio, J.,Rubio-Martinez, J.,Le Romancer, M.,Aytes, A.,Fuentes-Prior, P.,Estebanez-Perpina, E.
A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance.
Sci Adv, 9:eade2175-eade2175, 2023

PubMed 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 increases exposure of a major methylation target, Arg. We also corroborate the relevance of residues Arg and Tyr for AR dimerization and function. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine.

PubMed: 36921044
DOI: 10.1126/sciadv.ade2175

実験手法

X-RAY DIFFRACTION (1.4 Å)