US EPA

7423070 

Journal Article 

Boc3Arg-Linked Ligands Induce Degradation by Localizing Target Proteins to the 20S Proteasome 

Shi, Y; Long, MJ; Rosenberg, MM; Li, S; Kobjack, A; Lessans, P; Coffey, RT; Hedstrom, L; , 

2016 

Yes 

ACS Chemical Biology
ISSN: 1554-8929
EISSN: 1554-8937 

American Chemical Society 

11 

12 

3328-3337 

English 

27704767 

10.1021/acschembio.6b00656 

WOS:000390179700016 

https://pubs.acs.org/doi/10.1021/acschembio.6b00656
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Targeted protein degradation is a promising strategy for drug design and functional assessment. Several small molecule approaches have been developed that localize target proteins to ubiquitin ligases, inducing ubiquitination and subsequent degradation by the 26S proteasome. We discovered that the degradation of a target protein can also be induced by a recognition ligand linked to tert-butyl carbamate (Boc3)-protected arginine (B3A). Here, we show that this process requires the proteasome but does not involve ubiquitination of the target protein. B3A does not perturb the structure of the target protein; instead, a B3A-ligand stabilizes its target protein. B3A ligands stimulate activity of purified 20S proteasome, demonstrating that the tag binds directly to the 20S proteasome. Moreover, purified 20S proteasome is sufficient to degrade target proteins in the presence of their respective B3A-linked recognition ligands. These observations suggest a simple model for B3A-mediated degradation wherein the B3A tag localizes target proteins directly to the 20S proteasome. Thus, B3A ligands are the first example of a ubiquitin-free strategy for targeted protein degradation. 

arginine; carbamic acid; proteasome; ubiquitin protein ligase; arginine; ATP dependent 26S protease; carbamic acid derivative; ligand; proteasome; t-butylcarbamate; Article; ligand binding; priority journal; protein binding; protein degradation; protein localization; protein stability; protein structure; protein targeting; ubiquitination; analogs and derivatives; chemistry; drug design; drug effects; HeLa cell line; human; metabolism; protein degradation; Arginine; Carbamates; Drug Design; HeLa Cells; Humans; Ligands; Proteasome Endopeptidase Complex; Proteolysis