8VLB

Crystal structure of EloBC-VHL-CDO1 complex bound to compound 4 molecular glue

Summary for 8VLB

• Entry DOI: 10.2210/pdb8vlb/pdb
• Related: 8VL9
• Descriptor: von Hippel-Lindau disease tumor suppressor, Elongin-B, Elongin-C, ... (8 entities in total)
• Functional Keywords: vhl, cdo1, vhl-small molecule-cdo1 ternary complex, degradation, apoptosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 66485.05

Authors

Shu, W.,Ma, X.,Tutter, A.,Buckley, D.,Golosov, A.,Michaud, G. (deposition date: 2024-01-11, release date: 2024-03-13, Last modification date: 2025-11-05)

Primary citation

Tutter, A.,Buckley, D.,Golosov, A.A.,Ma, X.,Shu, W.,McKay, D.J.J.,Darsigny, V.,Dovala, D.,Beckwith, R.,Solomon, J.,Rao, P.,Xu, L.,Fazal, A.,Lingel, A.,Wartchow, C.,Cobb, J.S.,Hachey, A.,Tullai, J.,Michaud, G.A.
A small-molecule VHL molecular glue degrader for cysteine dioxygenase 1.
Nat.Chem.Biol., 21:1688-1696, 2025

PubMed Abstract: The von Hippel-Lindau tumor suppressor gene product (pVHL) is an E3 ligase substrate receptor that binds proline-hydroxylated hypoxia-inducible factor HIF1α, leading to its ubiquitin-dependent degradation. By using protein arrays, we identified a small molecule that binds the HIF1α-binding pocket on pVHL and functions as a molecular glue degrader of the neosubstrate cysteine dioxygenase (CDO1) by recruiting it into the VHL-Cullin-RING E3 ligase complex and leading to its selective degradation. The CDO1-binding region involved in VHL recruitment was characterized through a combination of mutagenesis and protein-protein docking coupled with molecular-dynamics-based solvation analysis. The X-ray structure of the ternary complexes of VHL, CDO1 and degrader molecules confirms the binding region prediction and provides atomic insights into key molecular glue interactions.

PubMed: 40555806
DOI: 10.1038/s41589-025-01936-x

Experimental method

X-RAY DIFFRACTION (2.9 Å)