9OIQ

The von Hippel Lindau-ElonginB-ElonginC (VCB) complex with fragment 15

This is a non-PDB format compatible entry.

Summary for 9OIQ

• Entry DOI: 10.2210/pdb9oiq/pdb
• Descriptor: Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (9 entities in total)
• Functional Keywords: vhl, e3 ligase, fragment-based drug discovery, protein transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 175016.72

Authors

Amporndanai, K.,Katinas, J.M.,Chopra, A.,Fesik, S.W. (deposition date: 2025-05-06, release date: 2025-07-09, Last modification date: 2025-09-03)

Primary citation

Amporndanai, K.,Katinas, J.M.,Chopra, A.,Kayode, O.,Vadukoot, A.K.,Waterson, A.G.,Fesik, S.W.
NMR-Based Fragment Screen of the von Hippel-Lindau Elongin C&B Complex.
Acs Med.Chem.Lett., 16:1648-1654, 2025

PubMed Abstract: von Hippel-Lindau (VHL) is an E3 ligase that has been widely exploited for the development of PROTACs to induce degradation of disease-associated target proteins. Nearly all VHL-recruiting PROTACs contain a hydroxyproline moiety based on the endogenous peptide substrate that occupies the HIF1α-binding site of VHL. However, the development of orally bioavailable PROTACs with hydroxyproline-based VHL ligands remains a significant hurdle, due to both the hydroxyproline and the peptidic nature of the VHL ligand. Here, we describe an NMR-based fragment screen against the VHL-Elongin C-Elongin B (VCB) complex. Several hits were shown by X-ray crystallography to bind to the HIF1α active site in VHL of the VCB complex, which opens the possibility for the discovery of new nonhydroxyproline-based VHL ligands for use in VHL-recruiting PROTACs.

PubMed: 40832550
DOI: 10.1021/acsmedchemlett.5c00316

Experimental method

X-RAY DIFFRACTION (2.66 Å)