Abstract
AbstractThe 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.
Publisher
Cold Spring Harbor Laboratory