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Liver cancer multiomics reveals diverse protein kinase A disruptions convergently produce fibrolamellar hepatocellular carcinoma.
Nat Commun
December 2024
Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY, USA.
Fibrolamellar Hepatocellular Carcinoma (FLC) is a rare liver cancer characterized by a fusion oncokinase of the genes DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). A few FLC-like tumors have been reported showing other alterations involving PKA. To better understand FLC pathogenesis and the relationships among FLC, FLC-like, and other liver tumors, we performed a massive multi-omics analysis.
View Article and Find Full Text PDFConformational dynamics of the enzyme-substrate complex of protein kinase A with pseudosubstrate SP20 and adenosine triphosphate.
Biomed Khim
December 2024
Chemistry Department, Lomonosov Moscow State University, Moscow, Russia; Bach Institute of Biochemistry, Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences, Moscow, Russia.
The phosphorylation reaction, catalyzed by the enzyme protein kinase A (PKA), plays one of the key roles in the work of the glutamatergic system, primarily involved in memory functioning. The analysis of the dynamic behavior of the enzyme-substrate complex allows one to learn the mechanism of the enzymatic reaction. According to the results of classical molecular dynamics calculations followed by hierarchical clustering, the most preferred proton acceptor during the phosphorylation reaction catalyzed by PKA is the carboxyl group of the amino acid residue Asp166; however, the γ-phosphate group of ATP can also act as an acceptor.
View Article and Find Full Text PDFPTH1R Suppressed Apoptosis of Mesenchymal Progenitors in Mandibular Growth.
Int J Mol Sci
November 2024
Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China.
Genetic abnormalities of the parathyroid hormone 1 receptor (PTH1R) lead to profound craniomaxillofacial bone and dentition defects on account of inappropriate tissue metabolism and cellular differentiation. The coordinated activity of differentiation and viability in bone cells is indispensable for bone metabolism. Recent research demonstrates mesenchymal progenitors are responsive to PTH1R signaling for osteogenic differentiation, whereas the effect of PTH1R on cellular survival remains incompletely understood.
View Article and Find Full Text PDFNeurobeachin regulates receptor downscaling at GABAergic inhibitory synapses in a protein kinase A-dependent manner.
Commun Biol
December 2024
Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
GABAergic synapses critically modulate neuronal excitability, and plastic changes in inhibitory synaptic strength require reversible interactions between GABA receptors (GABARs) and their postsynaptic anchor gephyrin. Inhibitory long-term potentiation (LTP) depends on the postsynaptic recruitment of gephyrin and GABARs, whereas the neurotransmitter GABA can induce synaptic removal of GABARs. However, the mechanisms and players underlying plastic adaptation of synaptic strength are incompletely understood.
View Article and Find Full Text PDFInhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.
Sci Adv
December 2024
Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates.
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