6BYN

Crystal structure of WDR5-Mb(S4) monobody complex

Summary for 6BYN

• Entry DOI: 10.2210/pdb6byn/pdb
• Descriptor: WD repeat-containing protein 5, WDR5-binding Monobody, Mb(S4) (3 entities in total)
• Functional Keywords: beta-propeller, fibronectin, mll1, inhibitor, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 44087.89

Authors

Gupta, A.,Koide, S. (deposition date: 2017-12-21, release date: 2018-07-04, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.69 Å)