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
Reads0
Chats0
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
More filters
Journal ArticleDOI
An auxin-based degron system for the rapid depletion of proteins in nonplant cells
TL;DR: The auxin-inducible degron (AID) system allowed rapid and reversible degradation of target proteins in response to auxin and enabled us to generate efficient conditional mutants of essential proteins in yeast as well as cell lines derived from chicken, mouse, hamster, monkey and human cells, thus offering a powerful tool to control protein expression and study protein function.
Journal ArticleDOI
Phthalimide conjugation as a strategy for in vivo target protein degradation
Georg E. Winter,Dennis L. Buckley,Joshiawa Paulk,Justin M. Roberts,Amanda Souza,Sirano Dhe-Paganon,James E. Bradner +6 more
TL;DR: In this paper, a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival, was devised.
Journal ArticleDOI
Induced protein degradation: an emerging drug discovery paradigm
Ashton C. Lai,Craig M. Crews +1 more
TL;DR: Induced protein degradation has the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.
Journal ArticleDOI
Catalytic in vivo protein knockdown by small-molecule PROTACs
Daniel P. Bondeson,Alina Mares,Ian Edward David Smith,Ko Eunhwa,Sebastien Andre Campos,Afjal Hussain Miah,Katie E Mulholland,Natasha Routly,Dennis L. Buckley,Jeffrey L. Gustafson,Nico Zinn,Paola Grandi,Satoko Shimamura,Giovanna Bergamini,Maria Faelth-Savitski,Marcus Bantscheff,Carly S. Cox,Deborah A. Gordon,Ryan R. Willard,John J. Flanagan,Linda N. Casillas,Bartholomew J. Votta,Willem den Besten,Kristoffer Famm,Laurens Kruidenier,Paul S. Carter,John D. Harling,Ian Churcher,Craig M. Crews +28 more
TL;DR: Major improvements to the proteolysis targeting chimeras (PROTACs) method are described, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation.
Journal ArticleDOI
Ubiquitin Ligases: Structure, Function, and Regulation
Ning Zheng,Nitzan Shabek +1 more
TL;DR: Current progress in structure-function studies of ubiquitin ligases as well as exciting new discoveries of novel classes of E3s and diverse substrate recognition mechanisms are summarized.
References
More filters
Journal ArticleDOI
A miniaturized arrayed assay format for detecting small molecule-protein interactions in cells
TL;DR: The screening method presented here provides an efficient means of rapidly screening large numbers of ligands made by split-pool synthesis in both yeast and mammalian cells.
Journal ArticleDOI
Small molecule-dependent genetic selection in stochastic nanodroplets as a means of detecting protein-ligand interactions on a large scale
Allen J Borchardt,Stephen D. Liberles,Stephen R. Biggar,Gerald R. Crabtree,Stuart L. Schreiber +4 more
TL;DR: The technique described here should facilitate the discovery of new cell-permeable ligands, especially when combined with a positive selection assay that detects intracellular binding of small molecules to proteins.
Related Papers (5)
Catalytic in vivo protein knockdown by small-molecule PROTACs
Daniel P. Bondeson,Alina Mares,Ian Edward David Smith,Ko Eunhwa,Sebastien Andre Campos,Afjal Hussain Miah,Katie E Mulholland,Natasha Routly,Dennis L. Buckley,Jeffrey L. Gustafson,Nico Zinn,Paola Grandi,Satoko Shimamura,Giovanna Bergamini,Maria Faelth-Savitski,Marcus Bantscheff,Carly S. Cox,Deborah A. Gordon,Ryan R. Willard,John J. Flanagan,Linda N. Casillas,Bartholomew J. Votta,Willem den Besten,Kristoffer Famm,Laurens Kruidenier,Paul S. Carter,John D. Harling,Ian Churcher,Craig M. Crews +28 more