7SSE

Crystal structure of the WDR domain of human DCAF1 in complex with CYCA-117-70

7SSE の概要

• エントリーDOI: 10.2210/pdb7sse/pdb
• 分子名称: DDB1- and CUL4-associated factor 1, N-[(3R)-1-(3-fluorophenyl)piperidin-3-yl]-6-(morpholin-4-yl)pyrimidin-4-amine (3 entities in total)
• 機能のキーワード: wd-repeat, wdr, dcaf1, sgc, structural genomics, structural genomics consortium, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71543.32

構造登録者

Kimani, S.,Owen, J.,Li, A.,Dong, A.,Li, Y.,Hutchinson, A.,Seitova, A.,Shahani, V.M.,Schapira, M.,Arrowsmith, C.H.,Edwards, A.M.,Halabelian, L.,Structural Genomics Consortium (SGC) (登録日: 2021-11-10, 公開日: 2021-12-15, 最終更新日: 2023-11-22)

主引用文献

Kimani, S.W.,Owen, J.,Green, S.R.,Li, F.,Li, Y.,Dong, A.,Brown, P.J.,Ackloo, S.,Kuter, D.,Yang, C.,MacAskill, M.,MacKinnon, S.S.,Arrowsmith, C.H.,Schapira, M.,Shahani, V.,Halabelian, L.
Discovery of a Novel DCAF1 Ligand Using a Drug-Target Interaction Prediction Model: Generalizing Machine Learning to New Drug Targets.
J.Chem.Inf.Model., 63:4070-4078, 2023

PubMed Abstract: DCAF1 functions as a substrate recruitment subunit for the RING-type CRL4 and the HECT family EDVP E3 ubiquitin ligases. The WDR domain of DCAF1 serves as a binding platform for substrate proteins and is also targeted by HIV and SIV lentiviral adaptors to induce the ubiquitination and proteasomal degradation of antiviral host factors. It is therefore attractive both as a potential therapeutic target for the development of chemical inhibitors and as an E3 ligase that could be recruited by novel PROTACs for targeted protein degradation. In this study, we used a proteome-scale drug-target interaction prediction model, MatchMaker, combined with cheminformatics filtering and docking to identify ligands for the DCAF1 WDR domain. Biophysical screening and X-ray crystallographic studies of the predicted binders confirmed a selective ligand occupying the central cavity of the WDR domain. This study shows that artificial intelligence-enabled virtual screening methods can successfully be applied in the absence of previously known ligands.

PubMed: 37350740
DOI: 10.1021/acs.jcim.3c00082

実験手法

X-RAY DIFFRACTION (1.62 Å)