9GIO

Crystal structure of the VHL-EloC-EloB complex with a covalent compound bound to C77 of VHL.

This is a non-PDB format compatible entry.

Summary for 9GIO

• Entry DOI: 10.2210/pdb9gio/pdb
• Descriptor: Elongin-B, Isoform 2 of Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (6 entities in total)
• Functional Keywords: vhl, covalent, fragment, e3 ligase, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 42271.30

Authors

Collie, G.W. (deposition date: 2024-08-19, release date: 2025-03-26, Last modification date: 2025-04-30)

Primary citation

Lucas, S.C.C.,Xu, Y.,Hewitt, S.,Collie, G.W.,Fusani, L.,Kadamur, G.,Hadfield, T.E.,Su, N.,Truman, C.,Demanze, S.,Hao, H.,Phillips, C.
Discovery of a Series of Covalent Ligands That Bind to Cys77 of the Von Hippel-Lindau Tumor Suppressor Protein (VHL).
Acs Med.Chem.Lett., 16:693-699, 2025

PubMed Abstract: Most ligands for the Von Hippel-Lindau tumor suppressor (VHL) bind at the HIF-1α binding site. Ligands that bind to allosteric sites on VHL could be highly valuable for the field of protein degradation, therefore, a covalent hit identification campaign was run targeting Cys77 on VHL. Hit bound selectively to Cys77 on VHL and did not alkylate the reactive Cys89 on Elongin B. It showed time- and concentration-dependent labeling, with a / of 0.30 M s, and does not affect binding at the HIF-1α site. This hit ligand was optimized to afford compound which showed improved potency and labeling of VHL. An X-ray structure of a close analogue was determined revealing the compound binding in a shallow groove on the surface of VHL. These are the first small molecules that bind covalently to an allosteric site on VHL and provide a suitable starting point for further optimization.

PubMed: 40236540
DOI: 10.1021/acsmedchemlett.4c00582

Experimental method

X-RAY DIFFRACTION (1.486 Å)