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991.
Alice Lee-Dutra Danielle K. Wiener Kristen L. Arienti Jing Liu Neelakandha Mani Michael K. Ameriks Frank U. Axe Damara Gebauer Pragnya J. Desai Steven Nguyen Mike Randal Robin L. Thurmond Siquan Sun Lars Karlsson James P. Edwards Todd K. Jones Cheryl A. Grice 《Bioorganic & medicinal chemistry letters》2010,20(7):2370-2374
A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency. 相似文献
992.
Ming Yu Mike Lizarzaburu Holger Beckmann Richard Connors Kang Dai Katrin Haller Cong Li Lingming Liang Michelle Lindstrom Ji Ma Alykhan Motani Malgorzata Wanska Alex Zhang Leping Li Julio C. Medina 《Bioorganic & medicinal chemistry letters》2010,20(5):1758-1762
Piperazine-bisamide analogs were discovered as partial agonists of human growth hormone secretagogue receptor (GHSR) in a high throughput screen. The partial agonists were optimized for potency and converted into antagonists through structure–activity relationship (SAR) studies. The efforts also led to the identification of potent antagonist with favorable PK profile suitable as a tool compound for in vivo studies. 相似文献
993.
A molecular switch for photoperiod responsiveness in mammals 总被引:4,自引:0,他引:4
Dardente H Wyse CA Birnie MJ Dupré SM Loudon AS Lincoln GA Hazlerigg DG 《Current biology : CB》2010,20(24):2193-2198
994.
Monroe EB Kang S Kyere SK Li R Prevelige PE 《Structure (London, England : 1993)》2010,18(11):1483-1491
Following budding, HIV-1 virions undergo a maturation process where the Gag polyprotein in the immature virus is cleaved by the viral protease and rearranges to form the mature infectious virion. Despite the wealth of structures of isolated capsid domains and an in?vitro-assembled mature lattice, models of the immature lattice do not provide an unambiguous model of capsid-molecule orientation and no structural information is available for the capsid maturation pathway. Here we have applied hydrogen/deuterium exchange mass spectrometry to immature, mature, and mutant Gag particles (CA5) blocked at the final Gag cleavage event to examine the molecular basis of capsid assembly and maturation. Capsid packing arrangements were very similar for all virions, whereas immature and CA5 virions contained an additional intermolecular interaction at the hexameric, 3-fold axis. Additionally, the N-terminal β-hairpin was observed to form as a result of capsid-SP1 cleavage rather than driving maturation as previously postulated. 相似文献
995.
996.
Laschober GT Ruli D Hofer E Muck C Carmona-Gutierrez D Ring J Hutter E Ruckenstuhl C Micutkova L Brunauer R Jamnig A Trimmel D Herndler-Brandstetter D Brunner S Zenzmaier C Sampson N Breitenbach M Fröhlich KU Grubeck-Loebenstein B Berger P Wieser M Grillari-Voglauer R Thallinger GG Grillari J Trajanoski Z Madeo F Lepperdinger G Jansen-Dürr P 《Aging cell》2010,9(6):1084-1097
To identify new genetic regulators of cellular aging and senescence, we performed genome-wide comparative RNA profiling with selected human cellular model systems, reflecting replicative senescence, stress-induced premature senescence, and distinct other forms of cellular aging. Gene expression profiles were measured, analyzed, and entered into a newly generated database referred to as the GiSAO database. Bioinformatic analysis revealed a set of new candidate genes, conserved across the majority of the cellular aging models, which were so far not associated with cellular aging, and highlighted several new pathways that potentially play a role in cellular aging. Several candidate genes obtained through this analysis have been confirmed by functional experiments, thereby validating the experimental approach. The effect of genetic deletion on chronological lifespan in yeast was assessed for 93 genes where (i) functional homologues were found in the yeast genome and (ii) the deletion strain was viable. We identified several genes whose deletion led to significant changes of chronological lifespan in yeast, featuring both lifespan shortening and lifespan extension. In conclusion, an unbiased screen across species uncovered several so far unrecognized molecular pathways for cellular aging that are conserved in evolution. 相似文献
997.
Eric Bourhis Christine Tam Yvonne Franke J. Fernando Bazan James Ernst Jiyoung Hwang Mike Costa Andrea G. Cochran Rami N. Hannoush 《The Journal of biological chemistry》2010,285(12):9172-9179
Wnt/β-catenin signaling is initiated at the cell surface by association of secreted Wnt with its receptors Frizzled (Fz) and low density lipoprotein receptor-related protein 5/6 (LRP5/6). The study of these molecular interactions has been a significant technical challenge because the proteins have been inaccessible in sufficient purity and quantity. In this report we describe insect cell expression and purification of soluble mouse Fz8 cysteine-rich domain and human LRP6 extracellular domain and show that they inhibit Wnt/β-catenin signaling in cellular assays. We determine the binding affinities of Wnts and Dickkopf 1 (Dkk1) to the relevant co-receptors and reconstitute in vitro the Fz8 CRD·Wnt3a·LRP6 signaling complex. Using purified fragments of LRP6, we further show that Wnt3a binds to a region including only the third and fourth β-propeller domains of LRP6 (E3E4). Surprisingly, we find that Wnt9b binds to a different part of the LRP6 extracellular domain, E1E2, and we demonstrate that Wnt3a and Wnt9b can bind to LRP6 simultaneously. Dkk1 binds to both E1E2 and E3E4 fragments and competes with both Wnt3a and Wnt9b for binding to LRP6. The existence of multiple, independent Wnt binding sites on the LRP6 co-receptor suggests new possibilities for the architecture of Wnt signaling complexes and a model for broad-spectrum inhibition of Wnt/β-catenin signaling by Dkk1. 相似文献
998.
Wing-yiu Lee Peter Hampson Lydia Coulthard Farrah Ali Mike Salmon Janet M. Lord Dagmar Scheel-Toellner 《The Journal of biological chemistry》2010,285(31):23889-23898
Members of the protein kinase C (PKC) family of serine-threonine kinases are important regulators of immune cell survival. Ingenol 3-angelate (PEP005) activates a broad range of PKC isoforms and induces apoptosis in acute myeloid leukemia cells by activating the PKC isoform PKCδ. We show here that, in contrast to its effect on leukemic cells, PEP005 provides a strong survival signal to resting and activated human T cells. The antiapoptotic effect depends upon the activation of PKCθ. This PKC isoform is expressed in T cells but is absent in myeloid cells. Further studies of the mechanism involved in this process showed that PEP005 inhibited activated CD8+ T cell apoptosis through the activation of NFκB downstream of PKCθ, leading to increased expression of the antiapoptotic proteins Mcl-1 and Bcl-xL. Transfection of CD8+ T cells with dominant-negative PKCθ diminished the prosurvival effect of PEP005 significantly. Ectopic expression of PKCθ in the acute myeloid leukemia cell line NB4 turned their response to PEP005 from an increased to decreased rate of apoptosis. Therefore, in contrast to myeloid leukemia cells, PEP005 provides a strong survival signal to T cells, and the expression of functional PKCθ influences whether PKC activation leads to an anti- or proapoptotic outcome in the cell types tested. 相似文献
999.
Stein LY Yoon S Semrau JD Dispirito AA Crombie A Murrell JC Vuilleumier S Kalyuzhnaya MG Op den Camp HJ Bringel F Bruce D Cheng JF Copeland A Goodwin L Han S Hauser L Jetten MS Lajus A Land ML Lapidus A Lucas S Médigue C Pitluck S Woyke T Zeytun A Klotz MG 《Journal of bacteriology》2010,192(24):6497-6498
Methylosinus trichosporium OB3b (for "oddball" strain 3b) is an obligate aerobic methane-oxidizing alphaproteobacterium that was originally isolated in 1970 by Roger Whittenbury and colleagues. This strain has since been used extensively to elucidate the structure and function of several key enzymes of methane oxidation, including both particulate and soluble methane monooxygenase (sMMO) and the extracellular copper chelator methanobactin. In particular, the catalytic properties of soluble methane monooxygenase from M. trichosporium OB3b have been well characterized in context with biodegradation of recalcitrant hydrocarbons, such as trichloroethylene. The sequence of the M. trichosporium OB3b genome is the first reported from a member of the Methylocystaceae family in the order Rhizobiales. 相似文献
1000.
Pilsczek FH Salina D Poon KK Fahey C Yipp BG Sibley CD Robbins SM Green FH Surette MG Sugai M Bowden MG Hussain M Zhang K Kubes P 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(12):7413-7425
Neutrophil extracellular traps (NETs) are webs of DNA covered with antimicrobial molecules that constitute a newly described killing mechanism in innate immune defense. Previous publications reported that NETs take up to 3-4 h to form via an oxidant-dependent event that requires lytic death of neutrophils. In this study, we describe neutrophils responding uniquely to Staphylococcus aureus via a novel process of NET formation that did not require neutrophil lysis or even breach of the plasma membrane. The multilobular nucleus rapidly became rounded and condensed. During this process, we observed the separation of the inner and outer nuclear membranes and budding of vesicles, and the separated membranes and vesicles were filled with nuclear DNA. The vesicles were extruded intact into the extracellular space where they ruptured, and the chromatin was released. This entire process occurred via a unique, very rapid (5-60 min), oxidant-independent mechanism. Mitochondrial DNA constituted very little if any of these NETs. They did have a limited amount of proteolytic activity and were able to kill S. aureus. With time, the nuclear envelope ruptured, and DNA filled the cytoplasm presumably for later lytic NET production, but this was distinct from the vesicular release mechanism. Panton-Valentine leukocidin, autolysin, and a lipase were identified in supernatants with NET-inducing activity, but Panton-Valentine leukocidin was the dominant NET inducer. We describe a new mechanism of NET release that is very rapid and contributes to trapping and killing of S. aureus. 相似文献