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71.
Pawel Nowak Derek C. Cole Ann Aulabaugh Jonathan Bard Rajiv Chopra Rebecca Cowling Kristi Y. Fan Baihua Hu Steve Jacobsen Minakshi Jani Guixan Jin Mei-Chu Lo Michael S. Malamas Eric S. Manas Rani Narasimhan Peter Reinhart Albert J. Robichaud Joseph R. Stock Joan Subrath Kristine Svenson John W. Ellingboe 《Bioorganic & medicinal chemistry letters》2010,20(2):632-635
8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S1 to the S3 pocket. 相似文献
72.
Pawel Sledz Heping Zheng Krzysztof Murzyn Maksymilian Chruszcz Matthew D Zimmerman Mahendra D Chordia Andrzej Joachimiak Wladek Minor 《Protein science : a publication of the Protein Society》2010,19(7):1395-1404
Surface lysine methylation (SLM) is a technique for improving the rate of success of protein crystallization by chemically methylating lysine residues. The exact mechanism by which SLM enhances crystallization is still not clear. To study these mechanisms, and to analyze the conditions where SLM will provide the optimal benefits for rescuing failed crystallization experiments, we compared 40 protein structures containing N,N-dimethyl-lysine (dmLys) to a nonredundant set of 18,972 nonmethylated structures from the PDB. By measuring the relative frequency of intermolecular contacts (where contacts are defined as interactions between the residues in proximity with a distance of 3.5 Å or less) of basic residues in the methylated versus nonmethylated sets, dmLys-Glu contacts are seen more frequently than Lys-Glu contacts. Based on observation of the 10 proteins with both native and methylated structures, we propose that the increased rate of contact for dmLys-Glu is due to both a slight increase in the number of amine-carboxyl H-bonds and to the formation of methyl C–H···O interactions. By comparing the relative contact frequencies of dmLys with other residues, the mechanism by which methylation of lysines improves the formation of crystal contacts appears to be similar to that of Lys to Arg mutation. Moreover, analysis of methylated structures with the surface entropy reduction (SER) prediction server suggests that in many cases SLM of predicted SER sites may contribute to improved crystallization. Thus, tools that analyze protein sequences and mark residues for SER mutation may identify proteins with good candidate sites for SLM. 相似文献
73.
Baudrimont A Penkner A Woglar A Machacek T Wegrostek C Gloggnitzer J Fridkin A Klein F Gruenbaum Y Pasierbek P Jantsch V 《PLoS genetics》2010,6(11):e1001219
The Caenorhabditis elegans inner nuclear envelope protein matefin/SUN-1 plays a conserved, pivotal role in the process of genome haploidization. CHK-2-dependent phosphorylation of SUN-1 regulates homologous chromosome pairing and interhomolog recombination in Caenorhabditis elegans. Using time-lapse microscopy, we characterized the movement of matefin/SUN-1::GFP aggregates (the equivalent of chromosomal attachment plaques) and showed that the dynamics of matefin/SUN-1 aggregates remained unchanged throughout leptonene/zygotene, despite the progression of pairing. Movement of SUN-1 aggregates correlated with chromatin polarization. We also analyzed the requirements for the formation of movement-competent matefin/SUN-1 aggregates in the context of chromosome structure and found that chromosome axes were required to produce wild-type numbers of attachment plaques. Abrogation of synapsis led to a deceleration of SUN-1 aggregate movement. Analysis of matefin/SUN-1 in a double-strand break deficient mutant revealed that repair intermediates influenced matefin/SUN-1 aggregate dynamics. Investigation of movement in meiotic regulator mutants substantiated that proper orchestration of the meiotic program and effective repair of DNA double-strand breaks were necessary for the wild-type behavior of matefin/SUN-1 aggregates. 相似文献
74.
Pawel Mazur Tomasz Magdziarz Andrzej Bak Zdzislaw Chilmonczyk Teresa Kasprzycka-Guttman Irena Misiewicz-Krzemińska Katarzyna Skupińska Jaroslaw Polanski 《Journal of molecular modeling》2010,16(7):1205-1212
Isothiocyanates (ITC) are well-known chemopreventive agents extracted from vegetables. This activity results from the activation
of human oxidoreductase. In this letter, the uncompetitive activatory mechanism of ITC was investigated using docking and
molecular dynamics simulations. This indicates that NAD(P)H:quinone oxidoreductase can efficiently improve enzyme-substrate
recognition within the catalytic site if the ITC activator supports the interaction in the uncompetitive binding site. 相似文献
75.
76.
Blake C. Ballif Aaron Theisen Ryan N. Traylor Devon Lamb Thrush Caroline Astbury Dennis Bartholomew Kim L. McBride Robert E. Pyatt Kate Shane Wendy E. Smith William B. Gallentine M. Katharine Rudd Julia A. Keene Jean P. Pfotenhauer Pawel Stankiewicz Bassem A. Bejjani 《American journal of human genetics》2010,86(3):454-461
77.
Heisler MG Hamant O Krupinski P Uyttewaal M Ohno C Jönsson H Traas J Meyerowitz EM 《PLoS biology》2010,8(10):e1000516
Morphogenesis during multicellular development is regulated by intercellular signaling molecules as well as by the mechanical properties of individual cells. In particular, normal patterns of organogenesis in plants require coordination between growth direction and growth magnitude. How this is achieved remains unclear. Here we show that in Arabidopsis thaliana, auxin patterning and cellular growth are linked through a correlated pattern of auxin efflux carrier localization and cortical microtubule orientation. Our experiments reveal that both PIN1 localization and microtubule array orientation are likely to respond to a shared upstream regulator that appears to be biomechanical in nature. Lastly, through mathematical modeling we show that such a biophysical coupling could mediate the feedback loop between auxin and its transport that underlies plant phyllotaxis. 相似文献
78.
79.
80.
Alpha-melanocyte stimulating hormone (alpha-MSH) and ghrelin play significant yet opposite roles in the regulation of feeding: alpha-MSH inhibits, whereas ghrelin stimulates consumption. The two peptidergic systems may interact in the process of food intake control. A single report published thus far has shown that a synthetic agonist of the melanocortin receptors, MTII, injected in the hypothalamic paraventricular nucleus (PVN) decreases feeding generated by ghrelin. We found that very low doses of alpha-MSH and MTII administered ICV significantly reduced ghrelin-dependent hyperphagia. However, an endogenous molecule, alpha-MSH, infused in the PVN did not exert an inhibitory effect on ghrelin-induced consumption, whereas the effective dose of PVN MTII exceeded that necessary to decrease short-term deprivation-induced feeding. We conclude that it is likely that in feeding regulation alpha-MSH and ghrelin "interact" at the central nervous system level, but the involvement of the PVN in this interaction appears questionable. 相似文献