Primary Amine Tethered Small Molecules Promote the Degradation of X-Linked Inhibitor of Apoptosis Protein
| Autor: | Wayne J. Fairbrother, Sayumi Yamazoe, Ingrid E. Wertz, Nicole Blaquiere, Steven T. Staben, Willem den Besten, Domagoj Vucic, Kebing Yu, Melinda M. Mulvihill, Elizabeth Helgason, Erin C. Dueber, Kshitij Verma, Wilson Phung, Tatiana Goncharov, Sumit Prakash, Anita Izrael-Tomasevic |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular chemistry.chemical_classification DNA ligase Molecular Structure biology X-Linked Inhibitor of Apoptosis Protein General Chemistry Crystallography X-Ray Inhibitor of apoptosis Biochemistry Small molecule Catalysis In vitro XIAP Cell biology Small Molecule Libraries Colloid and Surface Chemistry chemistry Ubiquitin biology.protein Humans Inducer Amines Function (biology) |
| Zdroj: | Journal of the American Chemical Society. 143:10571-10575 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/jacs.1c05269 |
| Popis: | We hypothesized that the proximity-driven ubiquitylation of E3-interacting small molecules could affect the degradation of E3 ubiquitin ligases. A series of XIAP BIR2 domain-binding small molecules was modified to append a nucleophilic primary amine. This modification transforms XIAP binders into inducers of XIAP degradation. The degradation of XIAP is E1- and proteasome-dependent, dependent on the ligase function of XIAP, and is rescued by subtle modifications of the small molecule that would obviate ubiquitylation. We demonstrate in vitro ubiquitylation of the small molecule that is dependent on its interaction with XIAP. Taken together, these results demonstrate the designed ubiquitylation of an engineered small molecule and a novel approach for the degradation of E3 ubiquitin ligases. |
| Databáze: | OpenAIRE |
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