Conventional small-molecule drugs primarily operate by inhibiting protein function, but this approach is limited when proteins lack well-defined ligand-binding pockets. Targeted protein degradation (TPD) offers an alternative approach by harnessing cellular degradation pathways to eliminate specific proteins. Recent studies have expanded the potential of TPD by identifying additional E3 ligases, with DCAF16 emerging as a promising candidate for facilitating protein degradation through both proteolysis-targeting chimera (PROTAC) and molecular glue mechanisms. In this study, we revisited a previously reported compound and discovered that it covalently binds to DCAF16. We further optimized it into a FKBP12-targeting PROTAC, MC-25B. This PROTAC engages DCAF16 at cysteines C177-179, leading to the degradation of nuclear-localized FKBP12. We further demonstrated the versatility of this DCAF16 recruiter by degrading additional endogenous proteins. Compared to the first-generation DCAF16-based PROTAC, which was derived from a fragment electrophile, this DCAF16 recruiter-based PROTAC exhibits improved proteome-wide selectivity.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acschembio.4c00799 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Effects of Chemical Pretreatments of Wood Cellulose Nanofibrils on Protein Adsorption and Biological Outcomes.
ACS Appl Mater Interfaces
January 2025
Center of Translational Oral Research (TOR), Department of Clinical Dentistry, University of Bergen, Bergen 5009, Norway.
Wood-based nanocellulose is emerging as a promising nanomaterial in the field of tissue engineering due to its unique properties and versatile applications. Previously, we used TEMPO-mediated oxidation (TO) and carboxymethylation (CM) as chemical pretreatments prior to mechanical fibrillation of wood-based cellulose nanofibrils (CNFs) to produce scaffolds with different surface chemistries. The aim of the current study was to evaluate the effects of these chemical pretreatments on serum protein adsorption on 2D and 3D configurations of TO-CNF and CM-CNF and then to investigate their effects on cell adhesion, spreading, inflammatory mediator production , and the development of foreign body reaction (FBR) .
View Article and Find Full Text PDFActivation of the conserved Hippo kinases by inflammasome-triggered proteolytic cleavage controls programmed cell death in macrophages.
Proc Natl Acad Sci U S A
February 2025
Department of Biological Sciences, College of Liberal Arts and Sciences, Wayne State University, Detroit, MI 48202.
The mammalian Hippo kinases, MST1 and MST2, regulate organ development and suppress tumor formation by balancing cell proliferation and death. In macrophages, inflammasomes detect molecular patterns from invading pathogens or damaged host cells and trigger programmed cell death. In addition to lytic pyroptosis, the signatures associated with apoptosis are induced by inflammasome activation, but how the inflammasomes coordinate different cell death processes remains unclear.
View Article and Find Full Text PDFHomeobox protein MSX-1 restricts hepatitis B virus by promoting ubiquitin-independent proteasomal degradation of HBx protein.
PLoS Pathog
January 2025
Department of Infectious Diseases, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
Hepatitis B virus (HBV) X protein (HBx) is a key factor for regulating viral transcription and replication. We recently characterized homeobox protein MSX-1 (MSX1) as a host restriction factor that inhibits HBV gene expression and genome replication by directly binding to HBV enhancer II/core promoter (EnII/Cp) and suppressing its promoter and enhancer activities. Notably, HBx expression was observed to be repressed more drastically by MSX1 compared to other viral antigens.
View Article and Find Full Text PDFProtein kinase C iota (PKCι) and pVHL are both needed for lysosomal degradation of α5 integrin in renal carcinoma cells.
Mol Biol Rep
January 2025
Department of Biology, Adelphi University, One South Avenue, P.O. Box 701, Garden City, NY, 11530-0701, USA.
Background: von Hippel-Lindau (VHL) hereditary cancer syndrome is caused by mutations in the VHL tumor suppressor gene and is characterized by a predisposition to form various types of tumors, including renal cell carcinomas, hemangioblastomas, and pheochromocytomas. The protein products of the VHL gene, pVHL, are part of an ubiquitin ligase complex that tags hypoxia inducible factor alpha (HIF-α) for proteosomal degradation. pVHL has also been reported to bind to atypical protein kinase C (aPKC).
View Article and Find Full Text PDFRNA G-quadruplex structure-based PROTACs for targeted DHX36 protein degradation and gene activity modulation in mammalian cells.
Nucleic Acids Res
January 2025
Department of Chemistry and State Key Laboratory of Marine Pollution, City University of Hong Kong, Hong Kong SAR 999077, China.
RNA G-quadruplexes (rG4s) are non-canonical secondary nucleic acid structures found in the transcriptome. They play crucial roles in gene regulation by interacting with G4-binding proteins (G4BPs) in cells. rG4-G4BP complexes have been associated with human diseases, making them important targets for drug development.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!