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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Small molecule therapeutics targeting F-box proteins in cancer
TL;DR: How F-box proteins function in cancer and potential small molecule inhibitors for cancer therapy are reviewed and summarized.
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Modeling the CRL4A ligase complex to predict target protein ubiquitination induced by cereblon-recruiting PROTACs
Nan Bai,Kristin M. Riching,Aman Makaju,Hao Chen Wu,Timothy M. Acker,Shu Ching Ou,Yaru Zhang,Xiaomeng Shen,Daryl N. Bulloch,Huan Rui,Brad K. Gibson,Danette L. Daniels,Marjeta Urh,Brooke M. Rock,Sara C. Humphreys +14 more
TL;DR: In this paper , a structure-based computational approach was proposed to predict target protein ubiquitination induced by cereblon-based PROTACs by leveraging available structural information of the CRL4A ligase complex (CRBN/DDB1/CUL4A/Rbx1/NEDD8/E2/Ub).
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Development of a PDEδ‐Targeting PROTACs that Impair Lipid Metabolism
Michael Winzker,Alexandra Friese,Uwe Koch,Petra Janning,Slava Ziegler,Herbert Waldmann,Herbert Waldmann +6 more
TL;DR: In this paper, the prenyl-protein chaperone PDEδ modulates the localization of lipidated proteins in the cell, but current knowledge about its biological function is limited.
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VHL-based PROTACs as potential therapeutic agents: Recent progress and perspectives
TL;DR: Proteolysis targeting chimeras (PROTACs) are a novel drug discovery paradigm that has been widely used as biological tools and medicinal molecules with the potential of clinical application value.
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Aberrant Activation of NF-κB Signalling in Aggressive Lymphoid Malignancies.
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TL;DR: The knowledge gained from these studies may be exploited for the development of therapeutic strategies to inhibit aberrant NF-κB activity at the level of the transcription-factor subunits and their target genes, as global inhibition of the pathway is toxic.
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