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991.
Natali A. Minassian Alan Gibbs Amy Y. Shih Yi Liu Robert A. Neff Steven W. Sutton Tara Mirzadegan Judith Connor Ross Fellows Matthew Husovsky Serena Nelson Michael J. Hunter Mack Flinspach Alan D. Wickenden 《The Journal of biological chemistry》2013,288(31):22707-22720
Voltage-gated sodium channels (VGSCs) are essential to the normal function of the vertebrate nervous system. Aberrant function of VGSCs underlies a variety of disorders, including epilepsy, arrhythmia, and pain. A large number of animal toxins target these ion channels and may have significant therapeutic potential. Most of these toxins, however, have not been characterized in detail. Here, by combining patch clamp electrophysiology and radioligand binding studies with peptide mutagenesis, NMR structure determination, and molecular modeling, we have revealed key molecular determinants of the interaction between the tarantula toxin huwentoxin-IV and two VGSC isoforms, Nav1.7 and Nav1.2. Nine huwentoxin-IV residues (F6A, P11A, D14A, L22A, S25A, W30A, K32A, Y33A, and I35A) were important for block of Nav1.7 and Nav1.2. Importantly, molecular dynamics simulations and NMR studies indicated that folding was normal for several key mutants, suggesting that these amino acids probably make specific interactions with sodium channel residues. Additionally, we identified several amino acids (F6A, K18A, R26A, and K27A) that are involved in isoform-specific VGSC interactions. Our structural and functional data were used to model the docking of huwentoxin-IV into the domain II voltage sensor of Nav1.7. The model predicts that a hydrophobic patch composed of Trp-30 and Phe-6, along with the basic Lys-32 residue, docks into a groove formed by the Nav1.7 S1-S2 and S3-S4 loops. These results provide new insight into the structural and molecular basis of sodium channel block by huwentoxin-IV and may provide a basis for the rational design of toxin-based peptides with improved VGSC potency and/or selectivity. 相似文献
992.
Mass spectrometry analysis of Arabidopsis histone H3 reveals distinct combinations of post-translational modifications 总被引:4,自引:0,他引:4
Johnson L Mollah S Garcia BA Muratore TL Shabanowitz J Hunt DF Jacobsen SE 《Nucleic acids research》2004,32(22):6511-6518
Chromatin is regulated at many different levels, from higher-order packing to individual nucleosome placement. Recent studies have shown that individual histone modifications, and combinations thereof, play a key role in modulating chromatin structure and gene activity. Reported here is an analysis of Arabidopsis histone H3 modifications by nanoflow-HPLC coupled to electrospray ionization on a hybrid linear ion trap-Fourier transform mass spectrometer (LTQ/FTMS). We find that the sites of acetylation and methylation, in general, correlate well with other plants and animals. Two well-studied modifications, dimethylation of Lys-9 (correlated with silencing) and acetylation of Lys-14 (correlated with active chromatin) while abundant by themselves were rarely found on the same histone H3 tail. In contrast, dimethylation at Lys-27 and monomethylation at Lys-36 were commonly found together. Interestingly, acetylation at Lys-9 was found only in a low percentage of histones while acetylation of Lys-14 was very abundant. The two histone H3 variants, H3.1 and H3.2, also differ in the abundance of silencing and activating marks confirming other studies showing that the replication-independent histone H3 is enriched in active chromatin. 相似文献
993.
Tara Chand Yadav Naresh Kumar Utkarsh Raj Nidhi Goel Pritish Kumar Vardawaj Ramasare Prasad 《Journal of biomolecular structure & dynamics》2020,38(2):382-397
AbstractDrug discovery for a vigorous and feasible lead candidate is a challenging scientific mission as it requires expertise, experience, and huge investment. Natural products and their derivatives having structural diversity are renowned source of therapeutic agents since many years. Tyrosol (a natural phenylethanoid) has been extracted from olive oil, and its structure was confirmed by elemental analysis, FT-IR, FT-NMR, and single crystal X-ray crystallography. The conformational analysis for tyrosol geometry was performed by Gaussian 09 in terms of density functional theory. Validation of bond lengths and bond angles obtained experimentally as well as theoretically were performed with the help of curve fitting analysis, and values of correlation coefficient (R) obtained as 0.988 and 0.984, respectively. The charge transfer within the tyrosol molecule was confirmed by analysis of HOMO→LUMO molecular orbitals. In molecular docking with COX-2 (PDB ID: 5F1A), tyrosol was found to possess satisfactory binding affinity as compared to other NSAIDs (Aspirin, Ibuprofen, and Naproxen) and a COX-2 selective drug (Celecoxib). ADMET prediction, drug-likeness and bioactivity score altogether confirm the lead/drug like potential of tyrosol. Further investigation of simulation quality plot, RMSD and RMSF plots, ligands behavior plot as well as post simulation analysis manifest the consistency of 5F1A-tyrosol complex throughout the 20?ns molecular simulation process that signifies its compactness and stability within the receptor pocket. Abbreviations ADMET Absorption, Distribution, Metabolism, Excretion and Toxicity Å Angstrom COX-2 Cyclooxygenase-2 DFT Density Functional Theory DMF Dimethylformamide FMO Frontier Molecular Orbital FT-IR Fourier-transform Infrared Spectroscopy FT-NMR Nuclear Magnetic Resonance Spectroscopy HOMO Highest Occupied Molecular Orbital LUMO Lowest Unoccupied Molecular Orbital MD Molecular Dynamics NS Nanosecond NSAIDs Non-steroidal anti-inflammatory drugs OPE Osiris Property Explorer RMSD Root-Mean-Square Deviation RMSF Root Sean Square Fluctuation Communicated by Ramaswamy H. Sarma 相似文献
994.
Tara A. Schwetz 《生物化学与生物物理学报:生物膜》2010,1798(3):367-3327
Nerve and muscle action potential repolarization are produced and modulated by the regulated expression and activity of several types of voltage-gated K+ (Kv) channels. Here, we show that sialylated N-glycans uniquely impact gating of a mammalian Shaker family Kv channel isoform, Kv1.5, but have no effect on gating of a second Shaker isoform, Kv1.4. Each isoform contains one potential N-glycosylation site located along the S1-S2 linker; immunoblot analyses verified that Kv1.4 and Kv1.5 were N-glycosylated. The conductance-voltage (G-V) relationships and channel activation rates for two glycosylation-site deficient Kv1.5 mutants, Kv1.5N290Q and Kv1.5S292A, and for wild-type Kv1.5 expressed under conditions of reduced sialylation, were each shifted linearly by a depolarizing ∼ 18 mV compared to wild-type Kv1.5 activation. External divalent cation screening experiments suggested that Kv1.5 sialic acids contribute to an external surface potential that modulates Kv1.5 activation. Channel availability was unaffected by changes in Kv1.5 glycosylation or sialylation. The data indicate that sialic acid residues attached to N-glycans act through electrostatic mechanisms to modulate Kv1.5 activation. The sialic acids fully account for effects of N-glycans on Kv1.5 gating. Conversely, Kv1.4 gating was unaffected by changes in channel sialylation or following mutagenesis to remove the N-glycosylation site. Each phenomenon is unique for Kv1 channel isoforms, indicating that sialylated N-glycans modulate gating of homologous Kv1 channels through isoform-specific mechanisms. Such modulation is relevant to changes in action potential repolarization that occur as ion channel expression and glycosylation are regulated. 相似文献
995.
Obesity is an increasingly important health issue in both humans and animals and has been highly correlated as a risk factor for hyperglycemic conditions in humans. Naturally occurring obesity has been extensively studied in nonhuman primates with a focus on the development of biomarkers for characterizing overweight individuals and tracking the progression of obesity to conditions such as type 2 diabetes mellitus. Animal models have provided a basic understanding of metabolism and carbohydrate physiology, and continue to contribute to ongoing research of obesity and its adverse health effects. This review focuses on spontaneous obesity in rhesus and cynomolgus macaques as a model for human obesity and type 2 diabetes mellitus, including associated risk factors for the development of obesity and obesity-related health conditions. Little is known about preventive measures to minimize obesity while maintaining a healthy colony of macaques, and numerous complexities such as social status, feeding behaviors, timing of feeding, food distribution, and stress have been identified as contributing factors to overweight body condition in both single and group housed nonhuman primates. As in humans, increased body weight and obesity in macaques affect their overall health status. These conditions may interfere with the suitability of some animals in various studies unrelated to obesity. 相似文献
996.
Lucie H. Salwiczek Laurent Prét?t Lanila Demarta Darby Proctor Jennifer Essler Ana I. Pinto Sharon Wismer Tara Stoinski Sarah F. Brosnan Redouan Bshary 《PloS one》2012,7(11)
The insight that animals'' cognitive abilities are linked to their evolutionary history, and hence their ecology, provides the framework for the comparative approach. Despite primates renowned dietary complexity and social cognition, including cooperative abilities, we here demonstrate that cleaner wrasse outperform three primate species, capuchin monkeys, chimpanzees and orang-utans, in a foraging task involving a choice between two actions, both of which yield identical immediate rewards, but only one of which yields an additional delayed reward. The foraging task decisions involve partner choice in cleaners: they must service visiting client reef fish before resident clients to access both; otherwise the former switch to a different cleaner. Wild caught adult, but not juvenile, cleaners learned to solve the task quickly and relearned the task when it was reversed. The majority of primates failed to perform above chance after 100 trials, which is in sharp contrast to previous studies showing that primates easily learn to choose an action that yields immediate double rewards compared to an alternative action. In conclusion, the adult cleaners'' ability to choose a superior action with initially neutral consequences is likely due to repeated exposure in nature, which leads to specific learned optimal foraging decision rules. 相似文献
997.
Larry R. Brown Lisa M. Komoroske R. Wayne Wagner Tara Morgan-King Jason T. May Richard E. Connon Nann A. Fangue 《PloS one》2016,11(1)
Climate change is driving rapid changes in environmental conditions and affecting population and species’ persistence across spatial and temporal scales. Integrating climate change assessments into biological resource management, such as conserving endangered species, is a substantial challenge, partly due to a mismatch between global climate forecasts and local or regional conservation planning. Here, we demonstrate how outputs of global climate change models can be downscaled to the watershed scale, and then coupled with ecophysiological metrics to assess climate change effects on organisms of conservation concern. We employed models to estimate future water temperatures (2010–2099) under several climate change scenarios within the large heterogeneous San Francisco Estuary. We then assessed the warming effects on the endangered, endemic Delta Smelt, Hypomesus transpacificus, by integrating localized projected water temperatures with thermal sensitivity metrics (tolerance, spawning and maturation windows, and sublethal stress thresholds) across life stages. Lethal temperatures occurred under several scenarios, but sublethal effects resulting from chronic stressful temperatures were more common across the estuary (median >60 days above threshold for >50% locations by the end of the century). Behavioral avoidance of such stressful temperatures would make a large portion of the potential range of Delta Smelt unavailable during the summer and fall. Since Delta Smelt are not likely to migrate to other estuaries, these changes are likely to result in substantial habitat compression. Additionally, the Delta Smelt maturation window was shortened by 18–85 days, revealing cumulative effects of stressful summer and fall temperatures with early initiation of spring spawning that may negatively impact fitness. Our findings highlight the value of integrating sublethal thresholds, life history, and in situ thermal heterogeneity into global change impact assessments. As downscaled climate models are becoming widely available, we conclude that similar assessments at management-relevant scales will improve the scientific basis for resource management decisions. 相似文献
998.
Karyotypes were analyzed for 25 species from 14 genera of the subtribe Sarcanthinae. The karyotypes of representatives of the following genera were recorded for the first time: Acampe, Chilochista, Gastrochilus, Pelatantheria, Robiquetia, Sarcanthus, and Thrixspermum. Most of the small-flowered genera exhibited relatively symmetrical, primitive karyotypes which were difficult to distinguish. Intrageneric variations were encountered. The significance of karyotype analyses of the Sarcanthinae is briefly discussed. 相似文献
999.
Tara A. Latteman Jennifer E. Mead Molly A. DuVall Craig C. Bunting John M. Bevington 《Biotropica》2014,46(6):652-656
Little is known about antiherbivore defenses in non‐myrmecophyte Cecropia trees. We compare two non‐myrmecophyte Cecropia—Cecropia sciadophylla and Cecropia tacuna—with Cecropia membranacea, a myrmecophyte. High levels of chemical defenses in young leaves and physical toughness of mature leaves compensate for the absence of mutualistic ants in C. sciadophylla. Some C. tacuna trees produce trichilia and Müllerian bodies suggesting it has lost a mutualism with ants. 相似文献
1000.