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Functional Characterization of the SHIP1-Domains Regarding Their Contribution to Inositol 5-Phosphatase Activity.
Biomolecules
January 2025
Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
The Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1) is a multidomain protein consisting of two protein-protein interaction domains, the Src homology 2 (SH2) domain, and the proline-rich region (PRR), as well as three phosphoinositide-binding domains, the pleckstrin homology-like (PHL) domain, the 5-phosphatase (5PPase) domain, and the C2 domain. SHIP1 is commonly known for its involvement in the regulation of the PI3K/AKT signaling pathway by dephosphorylation of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P) at the D5 position of the inositol ring. However, the functional role of each domain of SHIP1 for the regulation of its enzymatic activity is not well understood.
View Article and Find Full Text PDFJiangzhi Granule Ameliorates JNK-Mediated Mitochondrial Dysfunction to Reduce Lipotoxic Liver Injury in NASH.
Diabetes Metab Syndr Obes
January 2025
Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
Purpose: Mitochondrial dysfunction mediated by c-Jun N-terminal kinase (JNK) plays an important role in lipotoxic liver injury in nonalcoholic steatohepatitis (NASH). This study aims to investigate the pharmacological mechanism of Jiangzhi Granule (JZG), a Chinese herbal formula against NASH, with a focus on its regulation of JNK signaling-mediated mitochondrial function.
Methods: Hepatocytes were induced by palmitic acid (PA) for 24 h to establish an in vitro lipotoxic model, which was simultaneously treated with either JZG or vehicle control.
Computational screening and molecular dynamics of natural compounds targeting the SH2 domain of STAT3: a multitarget approach using network pharmacology.
Mol Divers
January 2025
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, 576104, India.
SH2 (Src Homology 2) domains play a crucial role in phosphotyrosine-mediated signaling and have emerged as promising drug targets, particularly in cancer therapy. STAT3 (Signal Transducer and Activator of Transcription 3), which contains an SH2 domain, plays a pivotal role in cancer progression and immune evasion because it facilitates the dimerization of STAT3, which is essential for their activation and subsequent nuclear translocation. SH2 domain-mediated STAT3 inhibition disrupts this binding, reduces phosphorylation of STAT3, and impairs dimerization.
View Article and Find Full Text PDFThe structural influence of the oncogenic driver mutation N642H in the STAT5B SH2 domain.
Protein Sci
January 2025
Department of Physics, University of Toronto, Toronto, Ontario, Canada.
The point mutation N642H of the signal transducer and activator of transcription 5B (STAT5B) protein is associated with aggressive and drug-resistant forms of leukemia. This mutation is thought to promote cancer due to hyperactivation of STAT5B caused by increased stability of the active, parallel dimer state. However, the molecular mechanism leading to this stabilization is not well understood as there is currently no structure of the parallel dimer.
View Article and Find Full Text PDFDevelopment of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase.
Nat Commun
December 2024
Institute of Physiological Chemistry, Faculty of Medicine, Philipps University of Marburg, Marburg, Germany.
Article Synopsis
- Mirror-image proteins made from D-amino acids are promising for therapy due to their stability and minimal immune reactions.
- Development involves creating D-target proteins, selecting L-binders via phage display, and synthesizing D-binders that interact with the natural L-targets.
- The study focuses on D-monobodies with strong binding to the D-SH2 domain of the BCR::ABL1 kinase, showing potential for therapeutic applications by inhibiting its activity and functioning well in biological settings.
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