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81.
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Adler A Park YD Larsen P Nagarajan V Wollenberg K Qiu J Myers TG Williamson PR 《The Journal of biological chemistry》2011,286(23):20977-20990
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Mark J. Ammirati Kim M. Andrews David D. Boyer Anne M. Brodeur Dennis E. Danley Shawn D. Doran Bernard Hulin Shenping Liu R. Kirk McPherson Stephen J. Orena Janice C. Parker Jana Polivkova Xiayang Qiu Carolyn B. Soglia Judith L. Treadway Maria A. VanVolkenburg Donald C. Wilder David W. Piotrowski 《Bioorganic & medicinal chemistry letters》2009,19(7):1991-1995
A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC50 = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes. 相似文献
84.
本试验以206小麦为母本,二棱大麦旱燕3号和六棱大麦原早1号为父本进进杂交。结果表明,两个组合早期的胚胎发育基本上是正常的,前者成胚率为8.75%,后者为16.8%。胚乳核最早于授粉后3天开始形成细胞。当胚乳细胞充满囊后,很快就转入迅速解体,胚随即停止生长,没有能够进一步分化出器官来。胚乳于授粉15天后,几乎全部败育,胚亦相继夭亡。胚胎发育过程中的不正常现象普遍存在。主要是极核受精过程遭受破坏;合子和初生胚乳核发育停滞;原胚虽能正常发育而胚乳没有形成;胚乳细胞过早形成和迅速解体等。讨论了杂交不孕和胚乳败育的原因。同时,提出了幼胚离体培养的适宜时间。 相似文献
85.
RNA聚合酶Ⅱ最大亚基Rpb1的羧基端结构域(carboxyl-terminal repeat domain,CTD)是RNA聚合酶Ⅱ发挥转录延伸功能所必需的,对其执行精确的转录调节功能至关重要。酵母细胞周期蛋白依赖性激酶CTDK-I(carboxyl-terminal repeat domain kinase,CTDK-I)由CTK1、CTK2和CTK3组成,作用于RNA聚合酶Ⅱ羧基端结构域,动态磷酸化CTD的七肽重复序列(YSPTSPS)来调控转录和翻译。酵母中的特异性蛋白CTK3与特殊的细胞周期蛋白CTK2结合形成异二聚体,再与CTDK-I的催化亚基CTK1结合以调节其活性。CTK1作为细胞周期蛋白CDK(cyclin dependent kinase,CDK)的同源蛋白,其结构与功能的研究可拓展人们对CDK蛋白家族的认识;CTK2-CTK3复合物对CTK1调控机制的研究也可为细胞周期蛋白抑制剂的研发提供新的思路。本文简述了酵母CTDK-I的功能特点及其亚基的结构与功能以及亚基间的相互作用,并展望了CTDK-I复合物的研究前景。 相似文献
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Sun X Qiu J Strong SA Green LS Wasley JW Colagiovanni DB Mutka SC Blonder JP Stout AM Richards JP Chun L Rosenthal GJ 《Bioorganic & medicinal chemistry letters》2011,21(12):3671-3675
S-Nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach. 相似文献
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Riyaz A. Mir Aditya Bele Sameer Mirza Shashank Srivastava Appolinaire A. Olou Shalis A. Ammons Jun Hyun Kim Channabasavaiah B. Gurumurthy Fang Qiu Hamid Band Vimla Band 《Molecular and cellular biology》2016,36(6):886-899
Ecdysoneless (ECD) is an evolutionarily conserved protein whose germ line deletion is embryonic lethal. Deletion of Ecd in cells causes cell cycle arrest, which is rescued by exogenous ECD, demonstrating a requirement of ECD for normal mammalian cell cycle progression. However, the exact mechanism by which ECD regulates cell cycle is unknown. Here, we demonstrate that ECD protein levels and subcellular localization are invariant during cell cycle progression, suggesting a potential role of posttranslational modifications or protein-protein interactions. Since phosphorylated ECD was recently shown to interact with the PIH1D1 adaptor component of the R2TP cochaperone complex, we examined the requirement of ECD phosphorylation in cell cycle progression. Notably, phosphorylation-deficient ECD mutants that failed to bind to PIH1D1 in vitro fully retained the ability to interact with the R2TP complex and yet exhibited a reduced ability to rescue Ecd-deficient cells from cell cycle arrest. Biochemical analyses demonstrated an additional phosphorylation-independent interaction of ECD with the RUVBL1 component of the R2TP complex, and this interaction is essential for ECD''s cell cycle progression function. These studies demonstrate that interaction of ECD with RUVBL1, and its CK2-mediated phosphorylation, independent of its interaction with PIH1D1, are important for its cell cycle regulatory function. 相似文献