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Peter W. Glunz Xiaojun Zhang Yan Zou Indawati Delucca Alexandra H. Nirschl Xuhong Cheng Carolyn A. Weigelt Daniel L. Cheney Anzhi Wei Rushith Anumula Joseph M. Luettgen Alan R. Rendina Mark Harpel Gang Luo Robert Knabb Pancras C. Wong Ruth R. Wexler E. Scott Priestley 《Bioorganic & medicinal chemistry letters》2013,23(18):5244-5248
Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P′ binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype. 相似文献
996.
Carl R. Illig Carl L. Manthey Sanath K. Meegalla Mark J. Wall Jinsheng Chen Kenneth J. Wilson Renee L. DesJarlais Shelley K. Ballentine Carsten Schubert Carl S. Crysler Yanmin Chen Christopher J. Molloy Margery A. Chaikin Robert R. Donatelli Edward Yurkow Zhao Zhou Mark R. Player Bruce E. Tomczuk 《Bioorganic & medicinal chemistry letters》2013,23(23):6363-6369
Structure–activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats. 相似文献
997.
L. Szerszen S. Mukherjee L. Chollet‐Hinton H. Katayama B. L. Pentelute R. J. Collier M. T. Fisher 《Protein science : a publication of the Protein Society》2013,22(5):586-594
We have visualized by cryo‐electron microscopy (cryo‐EM) the complex of the anthrax protective antigen (PA) translocon and the N‐terminal domain of anthrax lethal factor (LFN) inserted into a nanodisc model lipid bilayer. We have determined the structure of this complex at a nominal resolution of 16 Å by single‐particle analysis and three‐dimensional reconstruction. Consistent with our previous analysis of negatively stained unliganded PA, the translocon comprises a globular structure (cap) separated from the nanodisc bilayer by a narrow stalk that terminates in a transmembrane channel (incompletely distinguished in this reconstruction). The globular cap is larger than the unliganded PA pore, probably due to distortions introduced in the previous negatively stained structures. The cap exhibits larger, more distinct radial protrusions, previously identified with PA domain three, fitted by elements of the NMFF PA prepore crystal structure. The presence of LFN, though not distinguished due to the seven‐fold averaging used in the reconstruction, contributes to the distinct protrusions on the cap rim volume distal to the membrane. Furthermore, the lumen of the cap region is less resolved than the unliganded negatively stained PA, due to the low contrast obtained in our images of this specimen. Presence of the LFN extended helix and N terminal unstructured regions may also contribute to this additional internal density within the interior of the cap. Initial NMFF fitting of the cryoEM‐defined PA pore cap region positions the Phe clamp region of the PA pore translocon directly above an internal vestibule, consistent with its role in toxin translocation. 相似文献
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《Molecular membrane biology》2013,30(8):369-385
AbstractThe Klotho gene was identified as an ‘aging suppressor' in mice. Overexpression of the Klotho gene extends lifespan and defective Klotho results in rapid aging and early death. Both the membrane and secreted forms of Klotho have biological activity that include regulatory effects on general metabolism and a more specific effect on mineral metabolism that correlates with its effect on aging. Klotho serves as a co-receptor for fibroblast growth factor (FGF), but it also functions as a humoral factor that regulates cell survival and proliferation, vitamin D metabolism, and calcium and phosphate homeostasis and may serve as a potential tumor suppressor. Moreover, Klotho protects against several pathogenic processes in a FGF23-independent manner. These processes include cancer metastasis, vascular calcification, and renal fibrosis. This review covers the recent advances in Klotho research and discusses novel Klotho-dependent mechanisms that are clinically relevant in aging and age-related diseases. 相似文献
1000.
油松天然次生林居群遗传多样性及与产地地理气候因子的关联分析 总被引:3,自引:0,他引:3
利用ISSR分子标记技术,分析了中国北部地区10个油松天然次生林居群的遗传多样性,以及与地理环境因子的相关性.研究结果表明:13条ISSR引物对250个个体扩增出137条谱带,平均多态位点百分率60.72%,不同居群的多态位点百分率差异明显;不同地理居群间的期望杂合度指数在0.2824-0.3702之间,平均为0.3210;Shannon多样性指数范围为0.1923-0.2490,平均为0.2165.居群间的遗传变异占居群总的遗传多样性的37.53%.经Mantel检验,居群间的地理距离和遗传距离间不存在显著相关性(r=0.069,p=0.360).聚类分析(UPGMA)表明,河南宝天曼(BTM)、承德大窝铺(DWP)、宁夏苏峪口(SYK)和甘肃冶力关(YLG)居群聚为一组,辽宁医巫闾山(YWL)、山西沁源灵空山(LKS)、陕西蔡家川林场(CJC)、山西和顺云龙公园(YLGY)和山西汶水三道川林场(SDC)居群为一组,山东蒙山(Ms)居群独立为一组.经分析发现,分布于我国地势二级、三级阶梯分界线区域的油松天然林( YWL、BTM、YLGY)遗传多样性水平高,位于分布区东西临界点居群(MS、YLG)遗传多样性水平低.经相关性分析,温度相关因子(年均温、1月均温、极端最低温)、海拔及年降雨量显著影响遗传多样性水平.油松天然居群分子变异存在一定的地理变异规律. 相似文献