Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.
Kathleen M. Sakamoto,Kyung Bo Kim,Akiko Kumagai,Frank Mercurio,Craig M. Crews,Raymond J. Deshaies +5 more
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TLDR
It is shown that MetAP-2 can be tethered to SCFβ-TRCP, ubiquitinated, and degraded in a Protac-1-dependent manner, which may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.Abstract:
The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the IκBα phosphopeptide that is recognized by the F-box protein β-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCFβ-TRCP, ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.read more
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Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs
TL;DR: Phospho-dependent proteolysis targeting chimeras (phosphoPROTACs), a method to couple the conditional degradation of targeted proteins to the activation state of particular kinase-signaling pathways, are introduced.
Journal ArticleDOI
PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery.
TL;DR: An overview of the main PROTAC‐based approaches that have been developed is provided and the promising opportunities and considerations for the application of this technology in therapies and drug discovery are discussed.
Journal ArticleDOI
Small‐Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System
Dennis L. Buckley,Craig M. Crews +1 more
TL;DR: With the ability to induce and inhibit the degradation of targeted proteins, small-molecule modulators of the UPS have the potential to significantly expand the druggable portion of the proteome beyond traditional targets, such as enzymes and receptors.
Journal ArticleDOI
Synthetic Biology-The Synthesis of Biology.
TL;DR: The in vitro design, synthesis, and transfer of complete genomes into host cells point to the future of synthetic biology: the creation of designer cells with tailored desirable properties for biomedicine and biotechnology.
Journal ArticleDOI
Specific Knockdown of Endogenous Tau Protein by Peptide-Directed Ubiquitin-Proteasome Degradation
Ting-Ting Chu,Na Gao,Qian-Qian Li,Pu-Guang Chen,Xi-Fei Yang,Yong-Xiang Chen,Yufen Zhao,Yan-Mei Li +7 more
TL;DR: A series of multifunctional molecules that contained Tau-recognition moieties and E3 ligase-binding moieties to enhance Tau degradation were designed and synthesized and TH006 had the highest activity of inducing Tau degradation by increasing its poly-ubiquitination.
References
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