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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Journal ArticleDOI
Non-Steroidal Androgen Receptor Antagonists and Prostate Cancer: A Survey on Chemical Structures Binding this Fast-Mutating Target.
Claudia Ferroni,Greta Varchi +1 more
TL;DR: This review covers a survey of most promising classes of non-steroidal androgen receptor antagonists, also providing insights on their mechanism of action and efficacy in treating prostate cancer.
Journal ArticleDOI
Inducible Protein Degradation to Understand Genome Architecture.
TL;DR: A review of recent advances in protein degradation, with a focus on chromatin structure, is presented in this paper, with an overview of E3 ligase/target pairings and central questions leading to the next generation of PROTACs with an expanded scope and generality.
Posted ContentDOI
BacPROTACs mediate targeted protein degradation in bacteria
F.E. Morreale,Kleine S,Julia Leodolter,Ovchinnikov S,Juliane Kley,Robert Kurzbauer,Hoi Dm,Anton Meinhart,Markus Hartl,David Haselbach,Markus Kaiser,Tim Clausen,Tim Clausen +12 more
TL;DR: In this article, small-molecule degraders, called BacPROTACs, were developed that bind to the substrate receptor of the ClpC:ClpP protease, priming neo-substrates for degradation.
Book ChapterDOI
Kinetic Detection of E3:PROTAC:Target Ternary Complexes Using NanoBRET Technology in Live Cells
TL;DR: In this article, cellular assays utilizing NanoBRET technology for the study of ternary complexes, showing examples with two most popular PROTAC E3 ligase components, VHL (von Hippel-Lindau disease tumor suppressor) and CRBN (Cereblon).
Journal ArticleDOI
Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets.
TL;DR: The successes and limitations of antibody inhibitors in cancer immunotherapy, as well as research progress on PROTAC- and lysosomal-dependent degradation of target proteins, are reviewed.
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