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921.
Serra-Maluquer Xavier Gazol Antonio Sangüesa-Barreda Gabriel Sánchez-Salguero Raúl Rozas Vicente Colangelo Michele Gutiérrez Emilia Camarero J. Julio 《Ecosystems》2019,22(6):1325-1337
Ecosystems - Warming-related growth decrease on southern Fagus sylvatica forests has been observed in different regions; however, whether it is a generalized fact or not remains unclear. Here we... 相似文献
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Jinyu Li Franziska Flick Patricia Verheugd Paolo Carloni Bernhard Lüscher Giulia Rossetti 《PloS one》2015,10(9)
Sirtuin 2 (SIRT2) is a NAD+-dependent deacetylase that has been associated with neurodegeneration and cancer. SIRT2 is composed of a central catalytic domain, the structure of which has been solved, and N- and C-terminal extensions that are thought to control SIRT2 function. However structural information of these N- and C-terminal regions is missing. Here, we provide the first full-length molecular models of SIRT2 in the absence and presence of NAD+. We also predict the structural alterations associated with phosphorylation of SIRT2 at S331, a modification that inhibits catalytic activity. Bioinformatics tools and molecular dynamics simulations, complemented by in vitro deacetylation assays, provide a consistent picture based on which the C-terminal region of SIRT2 is suggested to function as an autoinhibitory region. This has the capacity to partially occlude the NAD+ binding pocket or stabilize the NAD+ in a non-productive state. Furthermore, our simulations suggest that the phosphorylation at S331 causes large conformational changes in the C-terminal region that enhance the autoinhibitory activity, consistent with our previous findings that phosphorylation of S331 by cyclin-dependent kinases inhibits SIRT2 catalytic activity. The molecular insight into the role of the C-terminal region in controlling SIRT2 function described in this study may be useful for future design of selective inhibitors targeting SIRT2 for therapeutic applications. 相似文献
927.
Jessica Karlsson Carmine M. Morgillo Alessandro Deplano Giovanni Smaldone Emilia Pedone F. Javier Luque Mona Svensson Ettore Novellino Cenzo Congiu Valentina Onnis Bruno Catalanotti Christopher J. Fowler 《PloS one》2015,10(11)
Background
Combined fatty acid amide hydrolase (FAAH) and cyclooxygenase (COX) inhibition is a promising approach for pain-relief. The Flu-AM1 and Ibu-AM5 derivatives of flurbiprofen and ibuprofen retain similar COX-inhibitory properties and are more potent inhibitors of FAAH than the parent compounds. However, little is known as to the nature of their interaction with FAAH, or to the importance of their chirality. This has been explored here.Methodology/Principal Findings
FAAH inhibitory activity was measured in rat brain homogenates and in lysates expressing either wild-type or FAAHT488A-mutated enzyme. Molecular modelling was undertaken using both docking and molecular dynamics. The (R)- and (S)-enantiomers of Flu-AM1 inhibited rat FAAH with similar potencies (IC50 values of 0.74 and 0.99 μM, respectively), whereas the (S)-enantiomer of Ibu-AM5 (IC50 0.59 μM) was more potent than the (R)-enantiomer (IC50 5.7 μM). Multiple inhibition experiments indicated that both (R)-Flu-AM1 and (S)-Ibu-AM5 inhibited FAAH in a manner mutually exclusive to carprofen. Computational studies indicated that the binding site for the Flu-AM1 and Ibu-AM5 enantiomers was located between the acyl chain binding channel and the membrane access channel, in a site overlapping the carprofen binding site, and showed a binding mode in line with that proposed for carprofen and other non-covalent ligands. The potency of (R)-Flu-AM1 was lower towards lysates expressing FAAH mutated at the proposed carprofen binding area than in lysates expressing wild-type FAAH.Conclusions/Significance
The study provides kinetic and structural evidence that the enantiomers of Flu-AM1 and Ibu-AM5 bind in the substrate channel of FAAH. This information will be useful in aiding the design of novel dual-action FAAH: COX inhibitors. 相似文献928.
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Edyta Jermakowicz Ada Wrblewska Emilia Brzosko Pawe Mirski Toomas Hirse 《Botanical journal of the Linnean Society. Linnean Society of London》2015,178(1):138-154
We investigated the phylogeographical structure of the boreal‐montane orchid Malaxis monophyllos in its Eurasian geographical range. We analysed four sequences of plastid DNA (trnL, trnL–trnF, rps16 and accD‐psaI), resulting in 19 haplotypes and revealing a high level of intraspecific diversity (HD = 0.702 and π = 0.196 × 10−2), but showing a lack of phylogeographical structure. This pattern might be caused by multiple phenomena and processes, e.g. broad‐fronted recolonization with accompanying multi‐directional gene flow between populations and expansion from at least two refugial areas. Despite the lack of phylogeographical structure, three centres of haplotype diversity were indicated in the European part of the range of M. monophyllos. According to these data, alpine and lowland glacial refugia located between the ice sheets in the European Alps and the Scandinavian glaciers seem most likely to be in Europe. Moreover, models of climatically suitable areas during the Last Glacial Maximum (LGM) confirmed the Alps as a possible refuge, and indicated an opportunity for the persistence of M. monophyllos populations in Beringia and parts of Siberia. Using two models [Model for Interdisciplinary Research on Climate (MIROC) and Community Climate System Model (CCSM)], we predicted a significant reduction in climatically suitable areas for M. monophyllos in the future (2080). Our study also demonstrated that the biological features of M. monophyllos, including breeding system and dispersal mode, seem to be crucial in understanding its phylogeographical pattern. Our results also highlighted the importance of anthropogenic habitats as reservoirs of genetic diversity and alternative habitats for this species in the context of declining natural populations. © 2015 The Linnean Society of London, Botanical Journal of the Linnean Society, 2015, 178 , 138–154. 相似文献
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Emilia?L. Wu Yifei Qi Soohyung Park Sairam?S. Mallajosyula Alexander?D. MacKerell Jr. Jeffery?B. Klauda Wonpil Im 《Biophysical journal》2015,109(10):2090-2100
Prion diseases are fatal neurodegenerative disorders, which are characterized by the accumulation of misfolded prion protein (PrPSc) converted from a normal host cellular prion protein (PrPC). Experimental studies suggest that PrPC is enriched with α-helical structure, whereas PrPSc contains a high proportion of β-sheet. In this study, we report the impact of N-glycosylation and the membrane on the secondary structure stability utilizing extensive microsecond molecular dynamics simulations. Our results reveal that the HB (residues 173 to 194) C-terminal fragment undergoes conformational changes and helix unfolding in the absence of membrane environments because of the competition between protein backbone intramolecular and protein-water intermolecular hydrogen bonds as well as its intrinsic instability originated from the amino acid sequence. This initiation of the unfolding process of PrPC leads to a subsequent increase in the length of the HB-HC loop (residues 195 to 199) that may trigger larger rigid body motions or further unfolding around this region. Continuous interactions between prion protein and the membrane not only constrain the protein conformation but also decrease the solvent accessibility of the backbone atoms, thereby stabilizing the secondary structure, which is enhanced by N-glycosylation via additional interactions between the N-glycans and the membrane surface. 相似文献