8T55

Co-crystal structure of the WD-repeat domain of human WDR91 in complex with MR46654

8T55 の概要

• エントリーDOI: 10.2210/pdb8t55/pdb
• 分子名称: WD repeat-containing protein 91, N-[3-(4-chlorophenyl)oxetan-3-yl]-1-propanoyl-1,2,3,4-tetrahydroquinoline-5-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: wd-repeat, wdr, wdr91, sgc, covalent ligand, structural genomics, psi-2, protein structure initiative, structural genomics consortium, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 119806.07

構造登録者

Ahmad, H.,Zeng, H.,Dong, A.,Li, Y.,Yen, H.,Seitova, A.,Xu, J.,Feng, J.W.,Brown, P.J.,Santhakumar, V.,Ackloo, S.,Arrowsmith, C.H.,Edwards, A.M.,Halabelian, L.,Structural Genomics Consortium (SGC) (登録日: 2023-06-12, 公開日: 2023-07-05, 最終更新日: 2024-10-23)

主引用文献

Ahmad, S.,Xu, J.,Feng, J.A.,Hutchinson, A.,Zeng, H.,Ghiabi, P.,Dong, A.,Centrella, P.A.,Clark, M.A.,Guie, M.A.,Guilinger, J.P.,Keefe, A.D.,Zhang, Y.,Cerruti, T.,Cuozzo, J.W.,von Rechenberg, M.,Bolotokova, A.,Li, Y.,Loppnau, P.,Seitova, A.,Li, Y.Y.,Santhakumar, V.,Brown, P.J.,Ackloo, S.,Halabelian, L.
Discovery of a First-in-Class Small-Molecule Ligand for WDR91 Using DNA-Encoded Chemical Library Selection Followed by Machine Learning.
J.Med.Chem., 66:16051-16061, 2023

PubMed Abstract: WD40 repeat-containing protein 91 (WDR91) regulates early-to-late endosome conversion and plays vital roles in endosome fusion, recycling, and transport. WDR91 was recently identified as a potential host factor for viral infection. We employed DNA-encoded chemical library (DEL) selection against the WDR domain of WDR91, followed by machine learning to predict ligands from the synthetically accessible Enamine REAL database. Screening of predicted compounds identified a WDR91 selective compound , with a of 6 ± 2 μM by surface plasmon resonance. The co-crystal structure confirmed the binding of to the WDR91 side pocket, in proximity to cysteine 487, which led to the discovery of covalent analogues and . The covalent adduct formation for and was confirmed by intact mass liquid chromatography-mass spectrometry. The discovery of , , and , accompanying structure-activity relationship, and the co-crystal structures provide valuable insights for designing potent and selective chemical tools against WDR91 to evaluate its therapeutic potential.

PubMed: 37996079
DOI: 10.1021/acs.jmedchem.3c01471

実験手法

X-RAY DIFFRACTION (2.2 Å)