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71.
Proteins often undergo conformational changes when binding to each other. A major fraction of backbone conformational changes involves motion on the protein surface, particularly in loops. Accounting for the motion of protein surface loops represents a challenge for protein-protein docking algorithms. A first step in addressing this challenge is to distinguish protein surface loops that are likely to undergo backbone conformational changes upon protein-protein binding (mobile loops) from those that are not (stationary loops). In this study, we developed a machine learning strategy based on support vector machines (SVMs). Our SVM uses three features of loop residues in the unbound protein structures-Ramachandran angles, crystallographic B-factors, and relative accessible surface area-to distinguish mobile loops from stationary ones. This method yields an average prediction accuracy of 75.3% compared with a random prediction accuracy of 50%, and an average of 0.79 area under the receiver operating characteristic (ROC) curve using cross-validation. Testing the method on an independent dataset, we obtained a prediction accuracy of 70.5%. Finally, we applied the method to 11 complexes that involve members from the Ras superfamily and achieved prediction accuracy of 92.8% for the Ras superfamily proteins and 74.4% for their binding partners. 相似文献
72.
Duan M Kazmierski WM Chong PY Deanda F Edelstein M Ferris R Peckham J Wheelan P Xiong Z Zhang H Nishizawa R Takaoka Y 《Bioorganic & medicinal chemistry letters》2011,21(21):6470-6475
A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles. 相似文献
73.
气孔导度(g)是控制冠层与大气之间能量和水分交换的重要因素。空气湿度是控制植物叶片气孔导度的一个关键环境因子。在过去的十几年中,普遍得到应用的是Ball-Woodrow-Berry(BWB)模型和Leuning模型中气孔导度与湿度的关系。本研究使用一个诊断变量f(H),基于农田叶片水平的光合-气孔导度观测数据,对BWB模型、Leuning模型以及新发展的power-h模型和power-D模型进行了气孔导度模拟效果的比较和评价。结果表明:BWB模型描述的是g和相对湿度(hs)之间的一种线性关系,当空气较为湿润时,模拟结果存在较大的低估;Leuning模型中反映的是g与饱和水汽压差(Ds)的非线性函数,降低了模拟结果的误差,但仍然不能很好地描述g在较湿状况下的显著升高;相比之下,两个新的模型,即Ds的指数函数和(1-hs)的指数函数形式模型能提高模拟结果的精度。这个研究结果也表明基于Ds的模型模拟效果要好于基于hs的模型。 相似文献
74.
Hui Meng Lifeng Tian Jie Zhou Zhiping Li Xuanmao Jiao Wayne W Li Markus Plomann Zhishun Xu Michael P Lisanti Chenguang Wang Richard G Pestell 《Cell cycle (Georgetown, Tex.)》2011,10(1):73-81
Cyclin D1 overexpression is a common feature of many human malignancies. Genomic deletion analysis has demonstrated a key role for cyclin D1 in cellular proliferation, angiogenesis and cellular migration. To investigate the mechanisms contributing to cyclin D1 functions, we purified cyclin D1a-associated complexes by affinity chromatography and identified the PACSIN 2 (protein kinase C and casein kinase substrate in neurons 2) protein by mass spectrometry. The PACSIN 2, but not the related PACSIN 1 and 3, directly bound wild-type cyclin D1 (cyclin D1a) at the carboxyl terminus and failed to bind cyclin D1b, the alternative splicing variant of cyclin D1. PACSIN 2 knockdown induced cellular migration and reduced cell spreading in LNCaP cells expressing cyclin D1a. In cyclin D1−/− mouse embryonic fibroblasts (MEFs), cyclin D1a, but not cyclin D1b, reduced the cell spreading to a polarized morphology. siPACSIN 2 had no effect on cellular migration of cyclin D1−/− MEFs. Cyclin D1a restored the migratory ability of cyclin D1−/− MEFs, which was further enhanced by knocking down PACSIN 2 with siRNA. The cyclin D1-associated protein, PACSIN 2, regulates cell spreading and migration, which are dependent on cyclin D1 expression.Key words: PACSIN 2, cyclin D1, polymorphism, cellular migration, cell spreading, cancer 相似文献
75.
In the present study, we designed a novel targeted multi-functional fusion protein LHAD composed of LL-37, FXa recognition peptide, hirudin-12-residue, AAP, and RGD peptide. It was expressed in the Pichia pastoris GS115 strain and purified by affinity chromatography. The in vitro studies suggested that the novel designed protein exhibited antibacterial activity, anti-platelet aggregation and anti-thrombin activities. Moreover, the capability of anti-thrombin was significantly increased compared to that of natural hirudin. Our study may provide a potential approach to design multi-functional drugs for the prevention and management of thrombosis. 相似文献
76.
PP2A activates brassinosteroid-responsive gene expression and plant growth by dephosphorylating BZR1 总被引:4,自引:0,他引:4
77.
Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma 总被引:1,自引:0,他引:1
Gu TL Deng X Huang F Tucker M Crosby K Rimkunas V Wang Y Deng G Zhu L Tan Z Hu Y Wu C Nardone J MacNeill J Ren J Reeves C Innocenti G Norris B Yuan J Yu J Haack H Shen B Peng C Li H Zhou X Liu X Rush J Comb MJ 《PloS one》2011,6(1):e15640
Cholangiocarcinoma, also known as bile duct cancer, is the second most common primary hepatic carcinoma with a median survival of less than 2 years. The molecular mechanisms underlying the development of this disease are not clear. To survey activated tyrosine kinases signaling in cholangiocarcinoma, we employed immunoaffinity profiling coupled to mass spectrometry and identified DDR1, EPHA2, EGFR, and ROS tyrosine kinases, along with over 1,000 tyrosine phosphorylation sites from about 750 different proteins in primary cholangiocarcinoma patients. Furthermore, we confirmed the presence of ROS kinase fusions in 8.7% (2 out of 23) of cholangiocarcinoma patients. Expression of the ROS fusions in 3T3 cells confers transforming ability both in vitro and in vivo, and is responsive to its kinase inhibitor. Our data demonstrate that ROS kinase is a promising candidate for a therapeutic target and for a diagnostic molecular marker in cholangiocarcinoma. The identification of ROS tyrosine kinase fusions in cholangiocarcinoma, along with the presence of other ROS kinase fusions in lung cancer and glioblastoma, suggests that a more broadly based screen for activated ROS kinase in cancer is warranted. 相似文献
78.
In eukaryotic cells, repair of DNA double-strand breaks (DSBs) by the nonhomologous end-joining (NHEJ) pathway is critical for genome stability. In contrast to the complex eukaryotic repair system, bacterial NHEJ apparatus consists of only two proteins, Ku and a multifunctional DNA ligase (LigD), whose functional mechanism has not been fully clarified. We show here for the first time that Sir2 is involved in the mycobacterial NHEJ repair pathway. Here, using tandem affinity purification (TAP) screening, we have identified an NAD-dependent deacetylase in mycobacteria which is a homologue of the eukaryotic Sir2 protein and interacts directly with Ku. Results from an in vitro glutathione S-transferase (GST) pull-down assay suggest that Sir2 interacts directly with LigD. Plasmid-based end-joining assays revealed that the efficiency of DSB repair in a sir2 deletion mutant was reduced 2-fold. Moreover, the Δsir2 strain was about 10-fold more sensitive to ionizing radiation (IR) in the stationary phase than the wild-type. Our results suggest that Sir2 may function closely together with Ku and LigD in the nonhomologous end-joining pathway in mycobacteria. 相似文献
79.
Poliovirus genomic RNA replication, protein translation, and virion assembly are performed in the cytoplasm of host cells. However, this does not mean that there is no relationship between poliovirus infection and the cellular nucleus. In this study, recombinant fluorescence-tagged poliovirus 3CD and 3C' proteins were shown to be expressed mainly in the cytoplasm of Vero cells in the absence of other viral proteins. However, upon poliovirus infection, many of these proteins redistributed to the nucleus, as well as to the cytoplasm. A series of transfection experiments revealed that the poliovirus 2A(pro) was responsible for the same redistribution of 3CD and 3C' proteins to the nucleus. Furthermore, a mutant 2A(pro) protein lacking protease activity abrogated this effect. The poliovirus 2A(pro) protein was also found to co-localize with the Nup153 protein, a component of the nuclear pore complexes on the nuclear envelope. These data provide further evidence that there are intrinsic interactions between poliovirus proteins and the cell nucleus, despite that many processes in the poliovirus replication cycle occur in the cytoplasm. 相似文献
80.