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21.
Dmitry Suplatov Kirill Kopylov Yana Sharapova 《Journal of biomolecular structure & dynamics》2019,37(8):2049-2060
Doramapimod (BIRB-796) is widely recognized as one of the most potent and selective type II inhibitors of human p38α mitogen-activated protein kinase (MAPK); however, the understanding of its binding mechanism remains incomplete. Previous studies indicated high affinity of the ligand to a so-called allosteric pocket revealed only in the ‘out’ state of the DFG motif (i.e. Asp168-Phe169-Gly170) when Phe169 becomes fully exposed to the solvent. The possibility of alternative binding in the DFG-in state was hypothesized, but the molecular mechanism was not known. Methods of bioinformatics, docking and long-time scale classical and accelerated molecular dynamics have been applied to study the interaction of Doramapimod with the human p38α MAPK. It was shown that Doramapimod can bind to the protein even when the Phe169 is fully buried inside the allosteric pocket and the kinase activation loop is in the DFG-in state. Orientation of the inhibitor in such a complex is significantly different from that in the known crystallographic complex formed by the kinase in the DFG-out state; however, the Doramapimod’s binding is followed by the ligand-induced conformational changes, which finally improve accommodation of the inhibitor. Molecular modelling has confirmed that Doramapimod combines the features of type I and II inhibitors of p38α MAPK, i.e. can directly and indirectly compete with the ATP binding. It can be concluded that optimization of the initial binding in the DFG-in state and the final accommodation in the DFG-out state should be both considered at designing novel efficient type II inhibitors of MAPK and homologous proteins.
Communicated by Ramaswamy H. Sarma 相似文献
22.
Kun Yang Min Fan Xiaohui Wang Jingjing Xu Yana Wang Fei Tu P. Spencer Gill Tuanzhu Ha Li Liu David L. Williams Chuanfu Li 《Cell death and differentiation》2022,29(1):133
High circulating levels of lactate and high mobility group box-1 (HMGB1) are associated with the severity and mortality of sepsis. However, it is unclear whether lactate could promote HMGB1 release during sepsis. The present study demonstrated a novel role of lactate in HMGB1 lactylation and acetylation in macrophages during polymicrobial sepsis. We found that macrophages can uptake extracellular lactate via monocarboxylate transporters (MCTs) to promote HMGB1 lactylation via a p300/CBP-dependent mechanism. We also observed that lactate stimulates HMGB1 acetylation by Hippo/YAP-mediated suppression of deacetylase SIRT1 and β-arrestin2-mediated recruitment of acetylases p300/CBP to the nucleus via G protein-coupled receptor 81 (GPR81). The lactylated/acetylated HMGB1 is released from macrophages via exosome secretion which increases endothelium permeability. In vivo reduction of lactate production and/or inhibition of GPR81-mediated signaling decreases circulating exosomal HMGB1 levels and improves survival outcome in polymicrobial sepsis. Our results provide the basis for targeting lactate/lactate-associated signaling to combat sepsis.Subject terms: Infectious diseases, Signal transduction, Epigenetics 相似文献
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The VS ribozyme trans-cleavage substrate interacts with the catalytic RNA via tertiary interactions. To study the role of phosphate groups in the ribozyme–substrate interaction, 18 modified substrates were synthesized, where an epimeric phosphorothioate replaces one of the phosphate diester linkages. Sites in the stem–loop substrate where phosphorothioate substitution impaired reaction cluster in two regions. The first site is the scissile phosphate diester linkage and nucleotides downstream of this and the second site is within the loop region. The addition of manganese ions caused recovery of the rate of reaction for phosphorothioate substitutions between A621 and A622 and U631 and C632, suggesting that these two phosphate groups may serve as ligands for two metal ions. In contrast, significant manganese rescue was not observed for the scissile phosphate diester linkage implying that electrophilic catalysis by metal ions is unlikely to contribute to VS ribozyme catalysis. In addition, an increase in the reaction rate of the unmodified VS ribozyme was observed when a mixture of magnesium and manganese ions acted as the cofactor. One possible explanation for this effect is that the cleavage reaction of the VS ribozyme is rate limited by a metal dependent docking of the substrate on the ribozyme. 相似文献
24.
Engelman DM Chen Y Chin CN Curran AR Dixon AM Dupuy AD Lee AS Lehnert U Matthews EE Reshetnyak YK Senes A Popot JL 《FEBS letters》2003,555(1):122-125
The folding of alpha-helical membrane proteins has previously been described using the two stage model, in which the membrane insertion of independently stable alpha-helices is followed by their mutual interactions within the membrane to give higher order folding and oligomerization. Given recent advances in our understanding of membrane protein structure it has become apparent that in some cases the model may not fully represent the folding process. Here we present a three stage model which gives considerations to ligand binding, folding of extramembranous loops, insertion of peripheral domains and the formation of quaternary structure. 相似文献
25.
The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1-cyclin B and Plk 总被引:7,自引:0,他引:7
The cyclosome/anaphase-promoting complex is a multisubunit ubiquitin ligase that targets for degradation mitotic cyclins and some other cell cycle regulators in exit from mitosis. It becomes enzymatically active at the end of mitosis. The activation of the cyclosome is initiated by its phosphorylation, a process necessary for its conversion to an active form by the ancillary protein Cdc20/Fizzy. Previous reports have implicated either cyclin-dependent kinase 1-cyclin B or polo-like kinase as the major protein kinase that directly phosphorylates and activates the cyclosome. These conflicting results could be due to the use of partially purified cyclosome preparations or of immunoprecipitated cyclosome, whose interactions with protein kinases or ancillary factors may be hampered by binding to immobilized antibody. To examine this problem, we have purified cyclosome from HeLa cells by a combination of affinity chromatography and ion exchange procedures. With the use of purified preparations, we found that both cyclin-dependent kinase 1-cyclin B and polo-like kinase directly phosphorylated the cyclosome, but the pattern of the phosphorylation of the different cyclosome subunits by the two protein kinases was not similar. Each protein kinase could restore only partially the cyclin-ubiquitin ligase activity of dephosphorylated cyclosome. However, following phosphorylation by both protein kinases, an additive and nearly complete restoration of cyclin-ubiquitin ligase activity was observed. It is suggested that this joint activation may be due to the complementary phosphorylation of different cyclosome subunits by the two protein kinases. 相似文献
26.
Four isoprenylated flavones, artoindonesianins Q-T, were isolated from the heartwood of Artocarpus champeden Roxb. The structures of these compounds were elucidated on the basis of their spectroscopic data. 相似文献
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About 25% of humans with chronic gastritis are negative for Helicobacter pylori, suggesting that other bacteria are capable of causing inflammation. Bacterial overgrowth may occur in the stomach under conditions of reduced acid secretion. In this review, we will explore what is generally known about non-H. pylori organisms and their ability to induce gastritis, with particular focus on Acinetobacter lwoffi. 相似文献
28.
Marco Sanchez-Guerra Yinan Zheng Citlalli Osorio-Yanez Jia Zhong Yana Chervona Sheng Wang Dou Chang John P McCracken Anaite Díaz Pier Alberto Bertazzi Petros Koutrakis Choong-Min Kang Xiao Zhang Wei Zhang Hyang-Min Byun Joel Schwartz Lifang Hou Andrea A Baccarelli 《Epigenetics》2015,10(7):633-642
Previous studies have reported epigenetic changes induced by environmental exposures. However, previous investigations did not distinguish 5-methylcytosine (5mC) from a similar oxidative form with opposite functions, 5-hydroxymethylcytosine (5hmC). Here, we measured blood DNA global 5mC and 5hmC by ELISA and used adjusted mixed-effects regression models to evaluate the effects of ambient PM10 and personal PM2.5 and its elemental components—black carbon (BC), aluminum (Al), calcium (Ca), potassium (K), iron (Fe), sulfur (S), silicon (Si), titanium (Ti), and zinc (Zn)—on blood global 5mC and 5hmC levels. The study was conducted in 60 truck drivers and 60 office workers in Beijing, China from The Beijing Truck Driver Air Pollution Study at 2 exams separated by one to 2 weeks. Blood 5hmC level (0.08%) was ∼83-fold lower than 5mC (6.61%). An inter-quartile range (IQR) increase in same-day PM10 was associated with increases in 5hmC of 26.1% in office workers (P = 0.004), 20.2% in truck drivers (P = 0.014), and 21.9% in all participants combined (P < 0.001). PM10 effects on 5hmC were increasingly stronger when averaged over 4, 7, and 14 d preceding assessment (up to 132.6% for the 14-d average in all participants, P < 0.001). PM10 effects were also significant after controlling for multiple testing (family-wise error rate; FWER < 0.05). 5hmC was not correlated with personal measures of PM2.5 and elemental components (FWER > 0.05). 5mC showed no correlations with PM10, PM2.5, and elemental components measures (FWER > 0.05). Our study suggests that exposure to ambient PM10 affects 5hmC over time, but not 5mC. This finding demonstrates the need to differentiate 5hmC and 5mC in environmental studies of DNA methylation. 相似文献
29.
Eliana M. Cancello Rogério R. Silva Alexandre Vasconcellos Yana T. Reis Luís M. Oliveira 《Biotropica》2014,46(4):441-450
In this study, we investigated the termites of the Brazilian Atlantic Forest, one of the most threatened biodiversity hotspots in the world, in regularly spaced sites from 7° S to 27° S latitude. To our knowledge, this is the only report of a latitudinal survey of termites at species level performed with a standardized sampling protocol. We evaluate termite diversity and abundance, and describe patterns of species composition based on feeding groups along the latitudinal gradient. We also describe the relative contribution of environmental variables to explain diversity patterns. Termite assemblages were investigated by standardized surveys at 15 Atlantic Forest sites, on six transects divided into five sections of 10 m², with 30 sections per site (or 300 m²/site), which were investigated by one trained person for one hour. Observed species richness and abundance were negatively correlated with latitude. The influence of latitude was explained mainly by variables related to temperature, precipitation and ambient energy (potential evapotranspiration). Our results also suggest that temperature exerts a greater constraint on Atlantic Forest termites than productivity, because ambient productivity increases with latitude in this forest but termite diversity decreases. Termite species richness in the Atlantic Forest showed a different pattern than those described for other organisms, increasing in diversity where the coastal‐forest strip narrows. Overall, our results indicate comparatively high termite species richness at northeastern sites and a significant impoverishment of termite assemblages in the southeastern and southern regions of the Atlantic Forest. 相似文献
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