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Journal of Cellular Physiology May 2024Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin-proteasome system to enable... (Review)
Review
Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin-proteasome system to enable targeted protein degradation, particularly impacting oncology. This review delves into the various types of PROTACs, such as peptide-based, nucleic acid-based, and small molecule PROTACs, each addressing distinct challenges in protein degradation. It also discusses innovative strategies like bridged PROTACs and conditional switch-activated PROTACs, offering precise targeting of previously "undruggable" proteins. The potential of PROTACs extends beyond oncology, with ongoing research and technological advancements needed to maximize their therapeutic potential. Future progress in this field relies on interdisciplinary collaboration and the integration of advanced computational tools to open new treatment avenues across various diseases.
Topics: Animals; Humans; Peptides; Proteasome Endopeptidase Complex; Proteolysis; Proteolysis Targeting Chimera; Ubiquitin
PubMed: 38501341
DOI: 10.1002/jcp.31255 -
Proceedings of the National Academy of... Oct 2023Gram-positive bacteria use SigI/RsgI-family sigma factor/anti-sigma factor pairs to sense and respond to cell wall defects and plant polysaccharides. In this signal...
Gram-positive bacteria use SigI/RsgI-family sigma factor/anti-sigma factor pairs to sense and respond to cell wall defects and plant polysaccharides. In this signal transduction pathway involves regulated intramembrane proteolysis (RIP) of the membrane-anchored anti-sigma factor RsgI. However, unlike most RIP signaling pathways, site-1 cleavage of RsgI on the extracytoplasmic side of the membrane is constitutive and the cleavage products remain stably associated, preventing intramembrane proteolysis. The regulated step in this pathway is their dissociation, which is hypothesized to involve mechanical force. Release of the ectodomain enables intramembrane cleavage by the RasP site-2 protease and activation of SigI. The constitutive site-1 protease has not been identified for any RsgI homolog. Here, we report that RsgI's extracytoplasmic domain has structural and functional similarities to eukaryotic SEA domains that undergo autoproteolysis and have been implicated in mechanotransduction. We show that site-1 proteolysis in and Clostridial RsgI family members is mediated by enzyme-independent autoproteolysis of these SEA-like domains. Importantly, the site of proteolysis enables retention of the ectodomain through an undisrupted β-sheet that spans the two cleavage products. Autoproteolysis can be abrogated by relief of conformational strain in the scissile loop, in a mechanism analogous to eukaryotic SEA domains. Collectively, our data support the model that RsgI-SigI signaling is mediated by mechanotransduction in a manner that has striking parallels with eukaryotic mechanotransducive signaling pathways.
Topics: Mechanotransduction, Cellular; Proteolysis; Bacillus subtilis; Cell Wall; Eukaryota
PubMed: 37756332
DOI: 10.1073/pnas.2310862120 -
European Journal of Medicinal Chemistry Nov 2023Inducing protein degradation by proteolysis targeting chimera (PROTAC) has provided great opportunities for scientific research and industrial applications. Histone... (Review)
Review
Inducing protein degradation by proteolysis targeting chimera (PROTAC) has provided great opportunities for scientific research and industrial applications. Histone deacetylase (HDAC)-PROTAC has been widely developed since the first report of its ability to induce the degradation of SIRT2 in 2017. To date, ten of the eighteen HDACs (HDACs 1-8, HDAC10, and SIRT2) have been successfully targeted and degraded by HDAC-PROTACs. HDAC-PROTACs surpass traditional HDAC inhibitors in many aspects, such as higher selectivity, more potent antiproliferative activity, and the ability to disrupt the enzyme-independent functions of a multifunctional protein and overcome drug resistance. Rationally designing HDAC-PROTACs is a main challenge in development because slight variations in chemical structure can lead to drastic effects on the efficiency and selectivity of the degradation. In the future, HDAC-PROTACs can potentially be involved in clinical research with the support of the increased amount of in vivo data, pharmacokinetic evaluation, and pharmacological studies.
Topics: Sirtuin 2; Histone Deacetylase Inhibitors; Proteolysis; Proteolysis Targeting Chimera
PubMed: 37607440
DOI: 10.1016/j.ejmech.2023.115746 -
Nature Structural & Molecular Biology Feb 2024Targeted protein degradation (TPD) by PROTAC (proteolysis-targeting chimera) and molecular glue small molecules is an emerging therapeutic strategy. To expand the roster...
Targeted protein degradation (TPD) by PROTAC (proteolysis-targeting chimera) and molecular glue small molecules is an emerging therapeutic strategy. To expand the roster of E3 ligases that can be utilized for TPD, we describe the discovery and biochemical characterization of small-molecule ligands targeting the E3 ligase KLHDC2. Furthermore, we functionalize these KLHDC2-targeting ligands into KLHDC2-based BET-family and AR PROTAC degraders and demonstrate KLHDC2-dependent target-protein degradation. Additionally, we offer insight into the assembly of the KLHDC2 E3 ligase complex. Using biochemical binding studies, X-ray crystallography and cryo-EM, we show that the KLHDC2 E3 ligase assembles into a dynamic tetramer held together via its own C terminus, and that this assembly can be modulated by substrate and ligand engagement.
Topics: Proteolysis; Ubiquitin-Protein Ligases; Ligands
PubMed: 38177675
DOI: 10.1038/s41594-023-01146-w -
Journal of Bacteriology Feb 2018Proteolysis is carefully regulated to prevent the untimely destruction of critical proteins. In this issue of the , Kim and colleagues identify YjfN as a proteolytic...
Proteolysis is carefully regulated to prevent the untimely destruction of critical proteins. In this issue of the , Kim and colleagues identify YjfN as a proteolytic regulator that stimulates the activity of the DegP/HtrA protease of (S. Kim, I. Song, G. Eom, and S. Kim, J Bacteriol 200:e00519-17, 2018, https://doi.org/10.1128/JB.00519-17). The suicide destruction and transcriptional regulation of YjfN limit its activity to conditions in which there are likely to be many misfolded substrate proteins present.
Topics: Escherichia coli; Escherichia coli Proteins; Heat-Shock Proteins; Periplasmic Proteins; Proteolysis; Suicide
PubMed: 29109189
DOI: 10.1128/JB.00639-17 -
Nature Chemical Biology Sep 2022
Topics: Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35995863
DOI: 10.1038/s41589-022-01124-1 -
Nature Reviews. Drug Discovery Nov 2022
Topics: Humans; Drug Discovery; Intercellular Signaling Peptides and Proteins; Proteolysis
PubMed: 36171334
DOI: 10.1038/d41573-022-00159-2 -
Nature Reviews. Drug Discovery Aug 2022
Topics: Drug Discovery; Humans; Intercellular Signaling Peptides and Proteins; Proteolysis
PubMed: 35787688
DOI: 10.1038/d41573-022-00112-3 -
Trends in Pharmacological Sciences Nov 2023
Topics: Humans; Proteolysis
PubMed: 37832526
DOI: 10.1016/j.tips.2023.09.004 -
Drug Discovery Today. Technologies Apr 2019
Topics: Drug Discovery; Proteins; Proteolysis; Small Molecule Libraries; Ubiquitination
PubMed: 31200853
DOI: 10.1016/j.ddtec.2019.04.002