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91.
Jiang W Tran JA Tucci FC Fleck BA Hoare SR Markison S Wen J Chen CW Marinkovic D Arellano M Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2007,17(23):6546-6552
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a K(i) of 11nM and an EC(50) of 24nM, while its 3R,4S-isomer 20f-2 exhibited a K(i) of 8.6 and an IC(50) of 65nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats. 相似文献
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Many signaling proteins are built from simple, modular components, yet display highly complex signal-processing behavior. Here we explore how modular domains can be used to build an ultrasensitive switch--a nonlinear input/output function that is central to many complex biological behaviors. By systematically altering the number and affinity of modular autoinhibitory interactions, we show that we can predictably convert a simple linear signaling protein into an ultrasensitive switch. 相似文献
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Comparison of topological clustering within protein networks using edge metrics that evaluate full sequence,full structure,and active site microenvironment similarity 下载免费PDF全文
Janelle B Leuthaeuser Stacy T Knutson Kiran Kumar Patricia C Babbitt Jacquelyn S Fetrow 《Protein science : a publication of the Protein Society》2015,24(9):1423-1439
The development of accurate protein function annotation methods has emerged as a major unsolved biological problem. Protein similarity networks, one approach to function annotation via annotation transfer, group proteins into similarity-based clusters. An underlying assumption is that the edge metric used to identify such clusters correlates with functional information. In this contribution, this assumption is evaluated by observing topologies in similarity networks using three different edge metrics: sequence (BLAST), structure (TM-Align), and active site similarity (active site profiling, implemented in DASP). Network topologies for four well-studied protein superfamilies (enolase, peroxiredoxin (Prx), glutathione transferase (GST), and crotonase) were compared with curated functional hierarchies and structure. As expected, network topology differs, depending on edge metric; comparison of topologies provides valuable information on structure/function relationships. Subnetworks based on active site similarity correlate with known functional hierarchies at a single edge threshold more often than sequence- or structure-based networks. Sequence- and structure-based networks are useful for identifying sequence and domain similarities and differences; therefore, it is important to consider the clustering goal before deciding appropriate edge metric. Further, conserved active site residues identified in enolase and GST active site subnetworks correspond with published functionally important residues. Extension of this analysis yields predictions of functionally determinant residues for GST subgroups. These results support the hypothesis that active site similarity-based networks reveal clusters that share functional details and lay the foundation for capturing functionally relevant hierarchies using an approach that is both automatable and can deliver greater precision in function annotation than current similarity-based methods. 相似文献
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Stacy Gelhaus Wendell Franca Golin-Bisello Sally Wenzel Robert W. Sobol Fernando Holguin Bruce A. Freeman 《The Journal of biological chemistry》2015,290(9):5868-5880
15-Hydroxyprostaglandin dehydrogenase (15PGDH) is the primary enzyme catalyzing the conversion of hydroxylated arachidonic acid species to their corresponding oxidized metabolites. The oxidation of hydroxylated fatty acids, such as the conversion of prostaglandin (PG) E2 to 15-ketoPGE2, by 15PGDH is viewed to inactivate signaling responses. In contrast, the typically electrophilic products can also induce anti-inflammatory and anti-proliferative responses. This study determined that hydroxylated docosahexaenoic acid metabolites (HDoHEs) are substrates for 15PGDH. Examination of 15PGDH substrate specificity was conducted in cell culture (A549 and primary human airway epithelia and alveolar macrophages) using chemical inhibition and shRNA knockdown of 15PGDH. Substrate specificity is broad and relies on the carbon position of the acyl chain hydroxyl group. 14-HDoHE was determined to be the optimal DHA substrate for 15PGDH, resulting in the formation of its electrophilic metabolite, 14-oxoDHA. Consistent with this, 14-HDoHE was detected in bronchoalveolar lavage cells of mild to moderate asthmatics, and the exogenous addition of 14-oxoDHA to primary alveolar macrophages inhibited LPS-induced proinflammatory cytokine mRNA expression. These data reveal that 15PGDH-derived DHA metabolites are biologically active and can contribute to the salutary signaling actions of Ω-3 fatty acids. 相似文献
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Stacy A. Bonos 《Journal of Phytopathology》2011,159(1):12-18
The dollar spot disease, incited by Sclerotinia homoeocarpa F.T. Bennet, is one of the most important diseases of creeping bentgrass (Agrostis stolonifera L.) on golf courses. An understanding of the inheritance of dollar spot resistance could enhance genetic improvement efforts in creeping bentgrass. The objectives of this study were to evaluate the response of two creeping bentgrass crosses to two different isolates of S. homoeocarpa, determine gene action and identify number of loci involved in resistance to individual fungal isolates. Parental clones, pseudo F2, pseudo F3, BC1 and BC2 progenies from two crosses were established in a field trial in a randomized complete block split‐plot design in the fall of 2002. Progeny of each generation (subplots) were inoculated with each of two isolates of S. homoeocarpa (main plots) applied at a rate of 0.25 g/m2 of prepared inoculum and evaluated for dollar spot disease. Minimum loci calculations averaged 1.0–2.6. Midparent heterosis calculations were not significant. Backcross population means were closest to the recurrent parent. Generation mean analysis supports a simple additive‐dominance model for both crosses and both isolates, although there was also some evidence of epistatic gene action depending on the cross and the isolate. These results confirm previous research that dollar spot disease is quantitatively inherited and indicate that there may be a few genes interacting in a mainly additive fashion to confer dollar spot disease resistance in creeping bentgrass. 相似文献