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排序方式: 共有598条查询结果,搜索用时 15 毫秒
111.
Peter Keov Laura López Shane M. Devine Celine Valant J. Robert Lane Peter J. Scammells Patrick M. Sexton Arthur Christopoulos 《The Journal of biological chemistry》2014,289(34):23817-23837
TBPB and 77-LH-28-1 are selective agonists of the M1 muscarinic acetylcholine receptor (mAChR) that may gain their selectivity through a bitopic mechanism, interacting concomitantly with the orthosteric site and part of an allosteric site. The current study combined site-directed mutagenesis, analytical pharmacology,and molecular modeling to gain further insights into the structural basis underlying binding and signaling by these agonists. Mutations within the orthosteric binding site caused similar reductions in affinity and signaling efficacy for both selective and prototypical orthosteric ligands. In contrast, the mutation of residues within transmembrane helix (TM) 2 and the second extracellular loop (ECL2) discriminated between the different classes of ligand. In particular, ECL2 appears to be involved in the selective binding of bitopic ligands and in coordinating biased agonism between intracellular calcium mobilization and ERK1/2 phosphorylation. Molecular modeling of the interaction between TBPB and the M1 mAChR revealed a binding pose predicted to extend from the orthosteric site up toward a putative allosteric site bordered by TM2, TM3, and TM7, thus consistent with a bitopic mode of binding. Overall, these findings provide valuable structural and mechanistic insights into bitopic ligand actions and receptor activation and support a role for ECL2 in dictating the active states that can be adopted by a G protein-coupled receptor. This may enable greater selective ligand design and development for mAChRs and facilitate improved identification of bitopic ligands. 相似文献
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Hiwa Majed Tatiana Johnston Celine Kelso Enrico Monachino Slobodan Jergic Nicholas E. Dixon Eleftherios Mylonakis Michael J. Kelso 《Bioorganic & medicinal chemistry letters》2018,28(22):3526-3528
Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious hospital-acquired infections and is responsible for significant morbidity and mortality in residential care facilities. New agents against MRSA are needed to combat rising resistance to current antibiotics. We recently reported 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC) as a new bacteriostatic agent against MRSA that appears to act via a novel mechanism. Here, twenty nine analogs of HMPC were synthesized, their anti-MRSA structure-activity relationships evaluated and selectivity versus human HKC-8 cells determined. Minimum inhibitory concentrations (MIC) ranged from 0.5 to 64?μg/mL and up to 16-fold selectivity was achieved. The 4-carbodithioate function was found to be essential for activity but non-specific reactivity was ruled out as a contributor to antibacterial action. The study supports further work aimed at elucidating the molecular targets of this interesting new class of anti-MRSA agents. 相似文献
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Brendon Conlan Rosemary Birch Celine Kelso Sophie Holland Amanda P. De Souza Stephen P. Long Jennifer L. Beck Spencer M. Whitney 《Plant, cell & environment》2019,42(4):1287-1301
The folding and assembly of Rubisco large and small subunits into L8S8 holoenzyme in chloroplasts involves many auxiliary factors, including the chaperone BSD2. Here we identify apparent intermediary Rubisco‐BSD2 assembly complexes in the model C3 plant tobacco. We show BSD2 and Rubisco content decrease in tandem with leaf age with approximately half of the BSD2 in young leaves (~70 nmol BSD2 protomer.m2) stably integrated in putative intermediary Rubisco complexes that account for <0.2% of the L8S8 pool. RNAi‐silencing BSD2 production in transplastomic tobacco producing bacterial L2 Rubisco had no effect on leaf photosynthesis, cell ultrastructure, or plant growth. Genetic crossing the same RNAi‐bsd2 alleles into wild‐type tobacco however impaired L8S8 Rubisco production and plant growth, indicating the only critical function of BSD2 is in Rubisco biogenesis. Agrobacterium mediated transient expression of tobacco, Arabidopsis, or maize BSD2 reinstated Rubisco biogenesis in BSD2‐silenced tobacco. Overexpressing BSD2 in tobacco chloroplasts however did not alter Rubisco content, activation status, leaf photosynthesis rate, or plant growth in the field or in the glasshouse at 20°C or 35°C. Our findings indicate BSD2 functions exclusively in Rubisco biogenesis, can efficiently facilitate heterologous plant Rubisco assembly, and is produced in amounts nonlimiting to tobacco growth. 相似文献
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Purina Ingrida Balode Maija Béchemin Christian Põder Tõnis Vérité Celine Maestrini Serge 《Hydrobiologia》2004,514(1-3):127-137
Hydrobiologia - A mesocosm experiment was used to investigate the effect of terrestrial-origin dissolved organic matter (DOM) on the development of dinoflagellates in natural summer phytoplankton... 相似文献
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Mathieu Gautier Junichi Yamaguchi Julien Foucaud Anne Loiseau Aurélien Ausset Benoit Facon Bernhard Gschloessl Jacques Lagnel Etienne Loire Hugues Parrinello Dany Severac Celine Lopez-Roques Cecile Donnadieu Maxime Manno Helene Berges Karim Gharbi Lori Lawson-Handley Lian-Sheng Zang Benjamin Prud’homme 《Current biology : CB》2018,28(20):3296-3302.e7
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Celine T. Goulet Marcus Michelangeli Melinda Chung Julia L. Riley Bob B. M. Wong Michael B. Thompson David G. Chapple 《Evolutionary ecology》2018,32(5):469-488
The pace-of-life syndrome (POLS) suggests that behavioral traits are correlated and integrate within a fast–slow physiological continuum. At the fast extreme, individuals having higher metabolic rates are more active, exploratory, and bold with the opposite suite of traits characterizing those at the slow physiological extreme. A recent framework suggests that behavioral types may also differ consistently in their cognitive style. Accordingly, we propose that cognition could be further incorporated into the POLS framework comprised of behavioral and thermal physiological traits. Under this premise, fast behavioral types having high thermal traits are predicted to acquire a novel task faster but at the cost of accuracy while slow behavioral types with low thermal traits would be more attentive, responding to cues at a slower rate leading to higher accuracy and flexibility. This was tested by measuring physiological and behavioral traits in delicate skinks (Lampropholis delicata) and testing their learning ability. Correlations were detected between cognition and behavior but not thermal physiology. Contrary to our predictions, individual positioning along these axes opposed our predicted directions along the fast–slow continuum. Fast lizards preferring lower body temperatures expressed higher activity, exploration, sociality, and boldness levels, and learned the discrimination learning task at a slower rate but made the most errors. Additionally, modelling results indicated that neither thermal physiology, behavior, or their interaction influenced cognitive performance. Although the small number of animals completing the final stages of the learning assays limits the strength of these findings. Thus, we propose that future research involving a greater sample size and number of trials be conducted so as to enhance our understanding into how the integration of cognitive style, behavior, and physiology may influence individual fitness within natural populations. 相似文献