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991.
It is shown that the photoemf in a pigmented membrane is specific to the magnesium-porphyrin conductance channel. A null current method was devised to measure directly the voltage dependence of the photoemf and the magnesium-porphyrin conductance. Their voltage dependence is in agreement with the hypothesis that the magnesium-porphyrin cation is the majority carrier 相似文献
992.
Inhibition of protein kinase activity is a focus of intense drug discovery efforts in several therapeutic areas. Major challenges facing the field include understanding of the factors determining the selectivity of kinase inhibitors and the development of compounds with the desired selectivity profile. Here, we report the analysis of sequence variability among high and low affinity targets of eight different small molecule kinase inhibitors (BIRB796, Tarceva, NU6102, Gleevec, SB203580, balanol, H89, PP1). It is observed that all high affinity targets of each inhibitor are found among a relatively small number of kinases, which have similar residues at the specific positions important for binding. The findings are highly statistically significant, and allow one to exclude the majority of kinases in a genome from a list of likely targets for an inhibitor. The findings have implications for the design of novel inhibitors with a desired selectivity profile (e.g. targeted at multiple kinases), the discovery of new targets for kinase inhibitor drugs, comparative analysis of different in vivo models, and the design of "a-la-carte" chemical libraries tailored for individual kinases. 相似文献
993.
Zoidis G Papanastasiou I Dotsikas I Sandoval A Dos Santos RG Papadopoulou-Daifoti Z Vamvakides A Kolocouris N Felix R 《Bioorganic & medicinal chemistry》2005,13(8):2791-2798
A facile preparation of 2-aminomethyl-2-tricyclo[3.3.1.1(1,7)]decaneacetic acid hydrochloride 5 (AdGABA) is described. The synthesis of AdGABA involves the hydrogenation of 2-cyano-2-tricyclo[3.3.1.1(1,7)]decaneacetic acid 11, which was synthesized by two different synthetic routes. AdGABA was found to antagonize the pentylenetetrazole (PTZ) and semicarbazide (SCZ) induced tonic convulsions and exhibits analgesic activity in the hot plate test on mice. Although its mechanism of action is quite similar to that proposed previously for gabapentin (interaction with the alpha2delta subunit of the voltage gated Ca2+ channels), further studies were undertaken in order to clarify the precise mechanism of the anticonvulsant and analgesic effects of AdGABA on a molecular level. 相似文献
994.
J-domain protein CDJ2 and HSP70B are a plastidic chaperone pair that interacts with vesicle-inducing protein in plastids 1 下载免费PDF全文
Liu C Willmund F Whitelegge JP Hawat S Knapp B Lodha M Schroda M 《Molecular biology of the cell》2005,16(3):1165-1177
J-domain cochaperones confer functional specificity to their heat shock protein (HSP)70 partner by recruiting it to specific substrate proteins. To gain insight into the functions of plastidic HSP70s, we searched in Chlamydomonas databases for expressed sequence tags that potentially encode chloroplast-targeted J-domain cochaperones. Two such cDNAs were found: the encoded J-domain proteins were named chloroplast DnaJ homolog 1 and 2 (CDJ1 and CDJ2). CDJ2 was shown to interact with a approximately 28-kDa protein that by mass spectrometry was identified as the vesicle-inducing protein in plastids 1 (VIPP1). In fractionation experiments, CDJ2 was detected almost exclusively in the stroma, whereas VIPP1 was found in low-density membranes, thylakoids, and in the stroma. Coimmunoprecipitation and mass spectrometry analyses identified stromal HSP70B as the major protein interacting with soluble VIPP1, and, as confirmed by cross-linking data, as chaperone partner of CDJ2. In blue native-PAGE of soluble cell extracts, CDJ2 and VIPP1 comigrated in complexes of >669, approximately 150, and perhaps approximately 300 kDa. Our data suggest that CDJ2, presumably via coiled-coil interactions, binds to VIPP1 and presents it to HSP70B in the ATP state. Our findings and the previously reported requirement of VIPP1 for the biogenesis of thylakoid membranes point to a role for the HSP70B/CDJ2 chaperone pair in this process. 相似文献
995.
Cilia-driven fluid flow in the zebrafish pronephros, brain and Kupffer's vesicle is required for normal organogenesis 总被引:6,自引:0,他引:6
Kramer-Zucker AG Olale F Haycraft CJ Yoder BK Schier AF Drummond IA 《Development (Cambridge, England)》2005,132(8):1907-1921
Cilia, as motile and sensory organelles, have been implicated in normal development, as well as diseases including cystic kidney disease, hydrocephalus and situs inversus. In kidney epithelia, cilia are proposed to be non-motile sensory organelles, while in the mouse node, two cilia populations, motile and non-motile have been proposed to regulate situs. We show that cilia in the zebrafish larval kidney, the spinal cord and Kupffer's vesicle are motile, suggesting that fluid flow is a common feature of each of these organs. Disruption of cilia structure or motility resulted in pronephric cyst formation, hydrocephalus and left-right asymmetry defects. The data show that loss of fluid flow leads to fluid accumulation, which can account for organ distension pathologies in the kidney and brain. In Kupffer's vesicle, loss of flow is associated with loss of left-right patterning, indicating that the 'nodal flow' mechanism of generating situs is conserved in non-mammalian vertebrates. 相似文献
996.
The dendritic trees of different neuronal types display an astonishing diversity in structure and function. How this diversity is generated remains incompletely understood. However, recent studies have revealed some of the underlying mechanisms by which intrinsic programs of cell-type specification and extrinsic factors exert their effects on the dendritic cytoskeleton to regulate patterns of growth and branching. 相似文献
997.
998.
Kempson J Pitts WJ Barbosa J Guo J Omotoso O Watson A Stebbins K Starling GC Dodd JH Barrish JC Felix R Fischer K 《Bioorganic & medicinal chemistry letters》2005,15(7):1829-1833
A series of fused pyrimidine based inhibitors of PDE7 have been derived from an earlier screening lead 1. The synthesis, structure-activity relationships (SAR) and selectivity against several other PDE family members are described. 相似文献
999.
Bao J Miao S Kayser F Kotliar AJ Baker RK Doss GA Felix JP Bugianesi RM Slaughter RS Kaczorowski GJ Garcia ML Ha SN Castonguay L Koo GC Shah K Springer MS Staruch MJ Parsons WH Rupprecht KM 《Bioorganic & medicinal chemistry letters》2005,15(2):447-451
Kv1.3, the voltage-gated potassium channel in human T cells, represents a new target for treating immunosuppression and autoimmune diseases. Correolide (1), a pentacyclic natural product, is a potent and selective Kv1.3 channel blocker. Simplification of correolide via removal of its E-ring generates enone 4, whose modification produced a new series of tetracyclic Kv1.3 blockers. The structure-activity relationship for this class of compounds in two functional assays, Rb_Kv and human T cell proliferation, is presented herein. The most potent analog 43 is 15-fold more potent than correolide as inhibitor of human T cell proliferation. 相似文献
1000.
Many lichen species produce both sexual and asexual propagules, but, aside from being minute, these diaspores lack special adaptations for long-distance dispersal. So far, molecular studies have not directly addressed isolation and genetic differentiation of lichen populations, both being affected by gene flow, at a regional scale. We used six mycobiont-specific microsatellite loci to investigate the population genetic structure of the epiphytic lichen Lobaria pulmonaria in two regions that strongly differed with respect to anthropogenic impact. In British Columbia, L. pulmonaria grows in continuous old-growth forests, while its populations in the old cultural landscape of Switzerland are comparably small and fragmented. Populations from both British Columbia and Switzerland were genetically diverse at the loci. Geographically restricted alleles, low historical gene flow, and analyses of genetic distance (upgma tree) and of differentiation (amova) indicated that populations from Vancouver Island and from the Canadian mainland were separated from each other, except for one, geographically intermediate population. This differentiation was attributed to different glacial and postglacial histories of coastal and inland populations in British Columbia. In contrast to expectations, the three investigated Swiss populations were genetically neither isolated nor differentiated from each other despite the long-lasting negative human impact on the lichen's range size in Central Europe. We propose that detailed studies integrating local landscape and regional scales are now needed to understand the processes of dispersal and gene flow in lichens. 相似文献