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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Two-Stage Strategy for Development of Proteolysis Targeting Chimeras and its Application for Estrogen Receptor Degraders
TL;DR: This proof-of-concept study demonstrates that the two-stage strategy can significantly facilitate the development of PROTACs against ER without the tedious process of making large numbers of PROTacs one by one.
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Systematic characterization of mutations altering protein degradation in human cancers.
Collin Tokheim,Xiaoqing Wang,Richard T. Timms,Richard T. Timms,Boning Zhang,Elijah L. Mena,Elijah L. Mena,Binbin Wang,Cynthia Chen,Jun Ge,Jun Chu,Wubing Zhang,Wubing Zhang,Stephen J. Elledge,Stephen J. Elledge,Myles Brown,X. Shirley Liu +16 more
TL;DR: In this paper, a deep learning model (deepDegron) was developed to identify mutations that result in degron loss and experimentally validated the prediction that gain-of-function truncating mutations in GATA3 and PPM1D result in increased protein stability.
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Protein-Catalyzed Capture Agents.
Heather D. Agnew,Matthew B. Coppock,Matthew N. Idso,Bert T. Lai,JingXin Liang,Amy M McCarthy-Torrens,Carmen M Warren,James R. Heath +7 more
TL;DR: The development of epitope-targeted PCCs was motivated by the desire to fully generalize pioneering work from the Sharpless and Finn groups in which in situ click screens were used to develop potent, divalent enzymatic inhibitors.
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A Bioorthogonal Small Molecule Selective Polymeric "Clickase"
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PROTACs: New method to degrade transcription regulating proteins.
Beichen Hu,Yirong Zhou,Dejuan Sun,Yueying Yang,Yang Liu,Xingzhou Li,Hua Li,Hua Li,Lixia Chen +8 more
TL;DR: In contrast to traditional inhibitors, PROTACs showed higher efficiency to tackle the diseases which were caused by protein overexpression due to their excellent performance for degrading target proteins in transcription regulation.
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