Discovery and structural characterization of a VHL-mediated molecular glue degrader targeting cysteine dioxygenase
Year: 2021
Type: article
Abstract: VHL is one of the most widely exploited E3 ligases to induce ubiquitination and subsequent targeted protein degradation. Although many VHL-mediated bifunctional proteolysis-targeting chimeras (PROTACs) are known in the literature, bona fide example of small molecule glue degrader that recruit client protein to interact with VHL remains scant. Here, we report a small molecular glue degrader discovered from protein microarrays. Using several biochemical, biophysical and cellular assays, we demonstrate these compounds induce neo-interactions between VHL and cysteine dioxygenase (CDO1), leading to the polyubiquitination and degradation of CDO1. Structural characterization of this VHL/CDO1/glue ternary complex maps the degron to a composite surface formed by multiple discontiguous regions of hCDO1. Collectively, our studies reveal the mechanism of action of a novel small molecular glue degrader that directly recruits CDO1 to VHL, presenting a new avenue for targeted protein degradation.
Author: Xiaolei Ma
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W3211005818