6BYN

Crystal structure of WDR5-Mb(S4) monobody complex

6BYN の概要

• エントリーDOI: 10.2210/pdb6byn/pdb
• 分子名称: WD repeat-containing protein 5, WDR5-binding Monobody, Mb(S4) (3 entities in total)
• 機能のキーワード: beta-propeller, fibronectin, mll1, inhibitor, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44087.89

構造登録者

Gupta, A.,Koide, S. (登録日: 2017-12-21, 公開日: 2018-07-04, 最終更新日: 2023-10-04)

主引用文献

Gupta, A.,Xu, J.,Lee, S.,Tsai, S.T.,Zhou, B.,Kurosawa, K.,Werner, M.S.,Koide, A.,Ruthenburg, A.J.,Dou, Y.,Koide, S.
Facile target validation in an animal model with intracellularly expressed monobodies.
Nat. Chem. Biol., 14:895-900, 2018

PubMed Abstract: Rapidly determining the biological effect of perturbing a site within a potential drug target could guide drug discovery efforts, but it remains challenging. Here, we describe a facile target validation approach that exploits monobodies, small synthetic binding proteins that can be fully functionally expressed in cells. We developed a potent and selective monobody to WDR5, a core component of the mixed lineage leukemia (MLL) methyltransferase complex. The monobody bound to the MLL interaction site of WDR5, the same binding site for small-molecule inhibitors whose efficacy has been demonstrated in cells but not in animals. As a genetically encoded reagent, the monobody inhibited proliferation of an MLL-AF9 cell line in vitro, suppressed its leukemogenesis and conferred a survival benefit in an in vivo mouse leukemia model. The capacity of this approach to readily bridge biochemical, structural, cellular characterization and tests in animal models may accelerate discovery and validation of druggable sites.

PubMed: 30013062
DOI: 10.1038/s41589-018-0099-z

実験手法

X-RAY DIFFRACTION (2.69 Å)