8T55

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

Summary for 8T55

• Entry DOI: 10.2210/pdb8t55/pdb
• Descriptor: 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)
• Functional Keywords: wd-repeat, wdr, wdr91, sgc, covalent ligand, structural genomics, psi-2, protein structure initiative, structural genomics consortium, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 119806.07

Authors

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) (deposition date: 2023-06-12, release date: 2023-07-05, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2 Å)