5LYQ

Crystal structure of the Retinoic Acid Receptor alpha in complex with a synthetic spiroketal agonist and a fragment of the TIF2 co-activator.

5LYQ の概要

• エントリーDOI: 10.2210/pdb5lyq/pdb
• 分子名称: Retinoic acid receptor RXR-alpha, HIS-LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN-ASP, (2~{R})-6,6,9,9-tetramethylspiro[3,4,7,8-tetrahydrobenzo[g]chromene-2,2'-3,4-dihydrochromene]-6'-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: nuclear receptor, rxr, spiroketal, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus : P19793
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28842.42

構造登録者

Andrei, S.A.,Ottmann, C. (登録日: 2016-09-28, 公開日: 2017-04-26, 最終更新日: 2024-01-17)

主引用文献

Scheepstra, M.,Andrei, S.A.,Unver, M.Y.,Hirsch, A.K.H.,Leysen, S.,Ottmann, C.,Brunsveld, L.,Milroy, L.G.
Designed Spiroketal Protein Modulation.
Angew. Chem. Int. Ed. Engl., 56:5480-5484, 2017

PubMed Abstract: Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure-based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co-activator recruitment. We solved the crystal structure of the spiroketal-hRXRα-TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co-crystal structure, the first of a designed spiroketal-protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes.

PubMed: 28407400
DOI: 10.1002/anie.201612504

実験手法

X-RAY DIFFRACTION (2.17 Å)