4OC7

Retinoic acid receptor alpha in complex with (E)-3-(3'-allyl-6-hydroxy-[1,1'-biphenyl]-3-yl)acrylic acid and a fragment of the coactivator TIF2

4OC7 の概要

• エントリーDOI: 10.2210/pdb4oc7/pdb
• 分子名称: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, (2E)-3-[6-hydroxy-3'-(prop-2-en-1-yl)biphenyl-3-yl]prop-2-enoic acid, ... (4 entities in total)
• 機能のキーワード: ligand binding domain, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus : P19793 Q15596
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30132.72

構造登録者

Leysen, S.,Scheepstra, M.,Brunsveld, L.,Milroy, L.G.,Ottmann, C. (登録日: 2014-01-08, 公開日: 2014-10-08, 最終更新日: 2024-02-28)

主引用文献

Scheepstra, M.,Nieto, L.,Hirsch, A.K.,Fuchs, S.,Leysen, S.,Lam, C.V.,in het Panhuis, L.,van Boeckel, C.A.,Wienk, H.,Boelens, R.,Ottmann, C.,Milroy, L.G.,Brunsveld, L.
A natural-product switch for a dynamic protein interface.
Angew.Chem.Int.Ed.Engl., 53:6443-6448, 2014

PubMed Abstract: Small ligands are a powerful way to control the function of protein complexes via dynamic binding interfaces. The classic example is found in gene transcription where small ligands regulate nuclear receptor binding to coactivator proteins via the dynamic activation function 2 (AF2) interface. Current ligands target the ligand-binding pocket side of the AF2. Few ligands are known, which selectively target the coactivator side of the AF2, or which can be selectively switched from one side of the interface to the other. We use NMR spectroscopy and modeling to identify a natural product, which targets the retinoid X receptor (RXR) at both sides of the AF2. We then use chemical synthesis, cellular screening and X-ray co-crystallography to split this dual activity, leading to a potent and molecularly efficient RXR agonist, and a first-of-kind inhibitor selective for the RXR/coactivator interaction. Our findings justify future exploration of natural products at dynamic protein interfaces.

PubMed: 24821627
DOI: 10.1002/anie.201403773

実験手法

X-RAY DIFFRACTION (2.5 Å)