2PIU

Androgen receptor LBD with small molecule

2PIU の概要

• エントリーDOI: 10.2210/pdb2piu/pdb
• 関連するPDBエントリー: 2PIN 2PIO 2PIP 2PIQ 2PIR 2PIT 2PIV 2PIW 2PIX 2PKL
• 分子名称: Androgen receptor, 5-ALPHA-DIHYDROTESTOSTERONE, [4-(4-HYDROXY-3-IODO-PHENOXY)-3,5-DIIODO-PHENYL]-ACETIC ACID, ... (4 entities in total)
• 機能のキーワード: androgen receptor inhibitors coactivator binding af-2, hormone receptor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : P10275
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30811.64

構造登録者

Estebanez-Perpina, E.,Arnold, A.A.,Baxter, J.D.,Webb, P.,Guy, R.K.,Fletterick, K.R. (登録日: 2007-04-13, 公開日: 2007-09-25, 最終更新日: 2024-02-21)

主引用文献

Estebanez-Perpina, E.,Arnold, L.A.,Arnold, A.A.,Nguyen, P.,Rodrigues, E.D.,Mar, E.,Bateman, R.,Pallai, P.,Shokat, K.M.,Baxter, J.D.,Guy, R.K.,Webb, P.,Fletterick, R.J.
A surface on the androgen receptor that allosterically regulates coactivator binding.
Proc.Natl.Acad.Sci.Usa, 104:16074-16079, 2007

PubMed Abstract: Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.

PubMed: 17911242
DOI: 10.1073/pnas.0708036104

実験手法

X-RAY DIFFRACTION (2.12 Å)