共查询到20条相似文献,搜索用时 15 毫秒
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Kaitlin Anstett Thibault Mesplede Maureen Oliveira Vincent Cutillas Mark A. Wainberg 《Journal of virology》2015,89(8):4681-4684
The new integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) displays limited cross-resistance with older drugs of this class and selects for the R263K substitution in treatment-experienced patients. We performed tissue culture selections with DTG, using viruses resistant to older INSTIs and infectivity and resistance assays, and showed that the presence of the E92Q or N155H substitution was compatible with the emergence of R263K, whereas the G140S Q148R, E92Q N155H, G140S, Y143R, and Q148R substitutions were not. 相似文献
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Jiaming Liang Thibault Mesplède Maureen Oliveira Kaitlin Anstett Mark A. Wainberg 《Journal of virology》2015,89(22):11269-11274
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The roles of K5 and K14 head, tail, and R/K L L E G E domains in keratin filament assembly in vitro 总被引:7,自引:0,他引:7 下载免费PDF全文
A rat cDNA encoding a 51-kD protein tyrosine phosphatase (PTP1) was cloned into a mammalian expression vector and transfected into normal and v-src-transformed mouse NIH 3T3 fibroblasts. In the stable subclones isolated, PTP1 expression at the mRNA level was elevated twofold to 25-fold. The highest constitutive level of phosphotyrosine-specific dephosphorylating activity observed without cytotoxic effects or significant clonal instability was approximately 10-fold over the endogenous activity. The expressed PTP1 was found to be associated with the particulate fraction of the fibroblasts. Subcellular fractionation and immunofluorescent microscopic examination of PTP1-overexpressing cells has shown the phosphatase to be localized to the reticular network of the ER. PTP1 was readily solubilized by detergents, but not by high salt. Limited proteolysis of membrane-associated PTP1 resulted in the release of lower molecular mass (48 and 37 kD) forms of the enzyme to the cytosol. Thermal phase partitioning of isolated membranes with Triton X-114 indicated that the full-length PTP1 was strongly integrated into the membrane in contrast to the proteolytically derived fragments of PTP1. Overexpression of PTP1 caused little apparent change in the rate of cell proliferation, but did induce changes in fibroblast morphology. A substantial increase in the proportion of bi- and multinucleate cells in PTP1-expressing cell populations was observed, and, in the case of the v-src-transformed cells, cell flattening and loss of refractibility occurred. Although no apparent difference in the tyrosine phosphorylation of pp60v-src was noted in v-src-transformed control and PTP1-overexpressing fibroblasts, the phosphotyrosine content of a 70-kD polypeptide was decreased in PTP1-overexpressing cells. 相似文献
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Muhammad Tahir Khan Muhammad Junaid Xueying Mao Yanjie Wang Abid Hussain Shaukat Iqbal Malik Dong-Qing Wei 《Journal of cellular biochemistry》2019,120(5):7154-7166
Pyrazinamide (PZA) is an important component of first-line antituberculosis drugs activated by Mycobacterium tuberculosis pyrazinamidase (PZase) into its active form pyrazinoic acid. Mutations in the pncA gene have been recognized as the major cause of PZA resistance. We detected some novel mutations, Leucine19Arginine (L19R), Arginine140Histidine (R140H), and Glutamic acid144 Lysine (E144K), in the pncA gene of PZA-resistant isolates in our wet lab PZA drug susceptibility testing and sequencing. As the molecular mechanism of resistance of these variants has not been reported earlier, we have performed multiple analyses to unveil different mechanisms of resistance because of PZase mutations L19R, R140H, and E144K. The mutants and native PZase structures were subjected to comprehensive computational molecular dynamics (MD) simulations at 100 nanoseconds in apo and drug-bound form. Mutants and native PZase binding pocket were compared to observe the consequence of mutations on the binding pocket size. Hydrogen bonding, Gibbs free energy, and natural ligand Fe +2 effect were also analyzed between native and mutants. A significant variation between native and mutant PZase structure activity was observed. The native PZase protein docking score was found to be the maximum, showing strong binding affinity in comparison with mutants. MD simulations explored the effect of the variants on the biological function of PZase. Hydrogen bonding, metal ion Fe +2 deviation, and fluctuation also seemed to be affected because of the mutations L19R, R140H, and E144K. The variants L19R, R140H, and E144K play a significant role in PZA resistance, altering the overall activity of native PZase, including metal ion Fe +2 displacement and free energy. This study offers valuable evidence for better management of drug-resistant tuberculosis. 相似文献
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Kaitlin Anstett Robert Fusco Vincent Cutillas Thibault Mesplède Mark A. Wainberg 《Journal of virology》2015,89(20):10482-10488
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Readers of this journal may ask themselves whether the worldreally needs another multi-author volume on transgenic crops.Indeed, I asked the same question myself when invited to reviewthis new 相似文献
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Sandrine Reigadas Guerric Anies Bernard Masquelier Christina Calmels Lieven J. Stuyver Vincent Parissi Herve Fleury Marie-Line Andreola 《PloS one》2010,5(4)
Resistance to HIV-1 integrase (IN) inhibitor raltegravir (RAL), is encoded by mutations in the IN region of the pol gene. The emergence of the N155H mutation was replaced by a pattern including the Y143R/C/H mutations in three patients with anti-HIV treatment failure. Cloning analysis of the IN gene showed an independent selection of the mutations at loci 155 and 143. Characterization of the phenotypic evolution showed that the switch from N155H to Y143C/R was linked to an increase in resistance to RAL. Wild-type (WT) IN and IN with mutations Y143C or Y143R were assayed in vitro in 3′end-processing, strand transfer and concerted integration assays. Activities of mutants were moderately impaired for 3′end-processing and severely affected for strand transfer. Concerted integration assay demonstrated a decrease in mutant activities using an uncleaved substrate. With 3′end-processing assay, IC50 were 0.4 µM, 0.9 µM (FC = 2.25) and 1.2 µM (FC = 3) for WT, IN Y143C and IN Y143R, respectively. An FC of 2 was observed only for IN Y143R in the strand transfer assay. In concerted integration, integrases were less sensitive to RAL than in ST or 3′P but mutants were more resistant to RAL than WT. 相似文献
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Ahmad Mohanad Esposto Josephine Golec Camilla Wu Colin Martic-Milne Sanela 《Molecular and cellular biochemistry》2021,476(6):2393-2408
Molecular and Cellular Biochemistry - Gelsolin, an actin-binding protein, is localized intra- and extracellularly in the bloodstream and throughout the body. Gelsolin amyloidosis is a disease... 相似文献
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Familial Mediterranean fever (FMF) is an autosomal recessive disorder caused by mutations in the Mediterranean fever gene (MEFV). We describe two novel missense mutations in MEFV, R653H and E230K. Both were found in compound heterozygosity with the mutation M694V in single Turkish patients with clinical syndromes characteristic for FMF. DNA sequencing and PCR-RFLP typing of the families confirmed the mutations and verified recessive modes of inheritance. 相似文献
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Ravi Shankar Bojja Mark D. Andrake George Merkel Steven Weigand Roland L. Dunbrack Jr. Anna Marie Skalka 《The Journal of biological chemistry》2013,288(10):7373-7386
We have applied small angle x-ray scattering and protein cross-linking coupled with mass spectrometry to determine the architectures of full-length HIV integrase (IN) dimers in solution. By blocking interactions that stabilize either a core-core domain interface or N-terminal domain intermolecular contacts, we show that full-length HIV IN can form two dimer types. One is an expected dimer, characterized by interactions between two catalytic core domains. The other dimer is stabilized by interactions of the N-terminal domain of one monomer with the C-terminal domain and catalytic core domain of the second monomer as well as direct interactions between the two C-terminal domains. This organization is similar to the “reaching dimer” previously described for wild type ASV apoIN and resembles the inner, substrate binding dimer in the crystal structure of the PFV intasome. Results from our small angle x-ray scattering and modeling studies indicate that in the absence of its DNA substrate, the HIV IN tetramer assembles as two stacked reaching dimers that are stabilized by core-core interactions. These models of full-length HIV IN provide new insight into multimer assembly and suggest additional approaches for enzyme inhibition. 相似文献
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