8t55 | pdb_00008t55
Co-crystal structure of the WD-repeat domain of human WDR91 in complex with MR46654
Structural highlights
FunctionWDR91_HUMAN Functions as a negative regulator of the PI3 kinase/PI3K activity associated with endosomal membranes via BECN1, a core subunit of the PI3K complex. By modifying the phosphatidylinositol 3-phosphate/PtdInsP3 content of endosomal membranes may regulate endosome fusion, recycling, sorting and early to late endosome transport (PubMed:26783301). It is for instance, required for the delivery of cargos like BST2/tetherin from early to late endosome and thereby participates indirectly to their degradation by the lysosome (PubMed:27126989). May play a role in meiosis (By similarity).[UniProtKB:Q7TMQ7][1] [2] Publication Abstract from PubMedWD40 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 1, with a K(D) of 6 +/- 2 muM by surface plasmon resonance. The co-crystal structure confirmed the binding of 1 to the WDR91 side pocket, in proximity to cysteine 487, which led to the discovery of covalent analogues 18 and 19. The covalent adduct formation for 18 and 19 was confirmed by intact mass liquid chromatography-mass spectrometry. The discovery of 1, 18, and 19, 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. Discovery of a First-in-Class Small-Molecule Ligand for WDR91 Using DNA-Encoded Chemical Library Selection Followed by Machine Learning.,Ahmad S, Xu J, Feng JA, Hutchinson A, Zeng H, Ghiabi P, Dong A, Centrella PA, Clark MA, Guie MA, Guilinger JP, Keefe AD, Zhang Y, Cerruti T, Cuozzo JW, von Rechenberg M, Bolotokova A, Li Y, Loppnau P, Seitova A, Li YY, Santhakumar V, Brown PJ, Ackloo S, Halabelian L J Med Chem. 2023 Dec 14;66(23):16051-16061. doi: 10.1021/acs.jmedchem.3c01471. , Epub 2023 Nov 23. PMID:37996079[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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