Tutter, Antonin, Buckley, Dennis, Golosov, Andrei, Ma, Xiaolei, Shu, Wei, Mckay, Daniel, Darsigny, Veronique, Dovala, Dustin, Beckwith, Rohan, Solomon, Jonathan, Rao, Pasupuleti, Xu, Lei, Fazal, Aleem, Lingel, Andreas, Wartchow, Charles, Cobb, Jennifer, Hachey, Amanda, Tullai, Jennifer and Michaud, Gregory (2024) A small molecule VHL molecular glue degrader for cysteine dioxygenase 1. bioXriv (first) and then Nature Chemical Biology (2nd).

Abstract

The Von Hippel-Lindau Tumor Suppressor gene product (pVHL) is an E3 ligase substrate receptor that binds proline-hydroxylated HIF1-α, leading to its ubiquitin-dependent degradation. By using protein arrays, we identified a small molecule that binds the HIF1-α 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.

Item Type:	Article
Date Deposited:	12 Mar 2024 00:45
Last Modified:	12 Mar 2024 00:45
URI:	https://oak.novartis.com/id/eprint/52801