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Molecular glue degraders (MGDs) and proteolysis-targeting chimeras (PROTACs) are two prominent approaches in targeted protein degradation, both leveraging the ubiquitin-proteasome system to induce selective protein degradation. While PROTACs rely on heterobifunctional motifs, MGDs possess more compact, mono-affinitive molecular structures, offering distinct advantages in drug-like properties. Over the past decade, significant progress has been made in development of MGDs, with over 20 MGDs advancing through clinical trials. Despite these advancements, the field remains in its early stages due to the novel mode of action and complex design principles. To facilitate rational design of MGDs, we present MolGlueDB, an open-access, web-based database consolidating information from 241 publications (January 2001-May 2025). MolGlueDB contains 1840 entries, including 1629 distinct MGDs, 28 recruiting proteins, and 94 targets, with comprehensive data on chemical structures, binding affinities, degradation capacities, biological activities, and physicochemical properties. The platform supports both text-based and structure-based searches, enabling users to refine results based on specific molecular attributes. MolGlueDB is freely accessible at https://www.molgluedb.com, providing a valuable resource for advancing research of MGDs and accelerating drug discovery in the field of targeted protein degradation.
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http://dx.doi.org/10.1093/nar/gkaf811 | DOI Listing |
Nano Lett
September 2025
Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha 410082, China.
Interleukin-12 (IL-12) is a robust proinflammatory cytokine that activates immune cells, such as T cells and natural killer cells, to induce antitumor immunity. However, the clinical application of recombinant IL-12 has been limited by systemic immune-related adverse events (irAEs) and rapid degradation. To address these challenges, we employed mRNA technology to encode a tumor-activated IL-12 "lock" fusion protein that offers both therapeutic efficacy and systemic safety.
View Article and Find Full Text PDFJ Virol
September 2025
Department of Pathology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Unlabelled: Oropouche fever is a debilitating disease caused by Oropouche virus (OROV), an arthropod-borne member of the Peribunyaviridae family. Despite its public health significance, the molecular mechanisms driving OROV pathogenesis remain poorly understood. In other bunyaviruses, the nonstructural NSs protein encoded by the small (S) genome segment acts as a major virulence factor.
View Article and Find Full Text PDFElife
September 2025
Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, India.
The UFD-1 (ubiquitin fusion degradation 1)-NPL-4 (nuclear protein localization homolog 4) heterodimer is involved in extracting ubiquitinated proteins from several plasma membrane locations, including the endoplasmic reticulum. This heterodimer complex helps in the degradation of ubiquitinated proteins via the proteasome with the help of the AAA+ATPase CDC-48. While the ubiquitin-proteasome system is known to have important roles in maintaining innate immune responses, the role of the UFD-1-NPL-4 complex in regulating immunity remains elusive.
View Article and Find Full Text PDFActa Crystallogr D Struct Biol
October 2025
Turkish Accelerator and Radiation Laboratory, 06830 Ankara, Türkiye.
Membrane-protein quality control in Escherichia coli involves coordinated actions of the AAA+ protease FtsH, the insertase YidC and the regulatory complex HflKC. These systems maintain proteostasis by facilitating membrane-protein insertion, folding and degradation. To gain structural insights into a putative complex formed by FtsH and YidC, we performed single-particle cryogenic electron microscopy on detergent-solubilized membrane samples, from which FtsH and YidC were purified using Ni-NTA affinity and size-exclusion chromatography.
View Article and Find Full Text PDFNew Phytol
September 2025
State Key Laboratory for Quality and Safety of Agro-Products, Key Laboratory of Biotechnology in Plant Protection of MARA, Zhejiang Key Laboratory of Green Plant Protection, Institute of Plant Virology, Ningbo University, Ningbo, 315211, China.
Our previous work identified p3-interacting protein (P3IP) as a novel plant factor that interacts with rice stripe virus p3 protein and activates autophagy to mediate its degradation, thereby restricting infection. However, the mechanism of P3IP-mediated autophagy and the evolutionary conservation of its antiviral function remain unknown. This study demonstrates that two Arabidopsis thaliana homologs, AtP3IP and AtP3IPH (Arabidopsis P3IP homologs, AtP3IPs), similarly activate autophagy and confer resistance to turnip mosaic virus (TuMV).
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