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
Citations
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PHOTACs enable optical control of protein degradation.
Martin Reynders,Martin Reynders,Bryan S. Matsuura,Marleen Bérouti,Marleen Bérouti,Daniele Simoneschi,Antonio Marzio,Michele Pagano,Dirk Trauner +8 more
TL;DR: The modular approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.
Journal ArticleDOI
Advancing targeted protein degradation for cancer therapy.
TL;DR: In this paper, the molecular basis of targeted protein degradation is discussed and a comprehensive review of the most promising degraders in development as cancer therapies to date is provided, with a focus on opportunities and challenges for future development.
Journal ArticleDOI
Tunable and reversible drug control of protein production via a self-excising degron.
Hokyung K. Chung,Conor L. Jacobs,Yunwen Huo,Jin Yang,Stefanie A. Krumm,Richard K. Plemper,Roger Y. Tsien,Michael Z. Lin +7 more
TL;DR: Small Molecule-Assisted Shutoff (SMASh), a technique in which proteins are fused to a degron that removes itself in the absence of drug, leaving untagged protein, is described.
Journal ArticleDOI
Degradation of proteins by PROTACs and other strategies.
TL;DR: Recent meaningful research of PROTAC is summarized, including the types of degradation proteins, preliminary biological data in vitro and in vivo, and new E3 ubiquitin ligases, which strongly proved the value of the PROTAC strategy.
Journal ArticleDOI
Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action.
Kristin M. Riching,Sarah D. Mahan,Cesear Corona,Mark McDougall,James D Vasta,Matthew B. Robers,Marjeta Urh,Danette L. Daniels +7 more
TL;DR: An innovative, modular live-cell platform utilizing endogenous tagging technologies is presented and applied to monitoring PROTAC-mediated degradation of the bromodomain and extra-terminal family members, showing comprehensive real-time degradation and recovery profiles for each target.
References
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