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71.
The EGF receptor transmembrane domain: peptide-peptide interactions in fluid bilayer membranes 下载免费PDF全文
A peptide containing the transmembrane domain of the human EGF receptor was studied in fluid lipid bilayers for insight into receptor tyrosine kinase lateral associations in cell membranes. The peptide comprised the 23-amino acid hydrophobic segment thought to span the membrane (Ile(622) to Met(644) of the EGF receptor), plus the first 10 amino acids of the receptor's cytoplasmic domain (Arg(645) to Thr(654)). Probes for solid-state NMR spectroscopy were incorporated by deuteration of the methyl side chains of alanine at positions 623 and 637. (2)H-NMR spectra were recorded from 25 to 65 degrees C in membranes composed of 1-palmitoyl-2-oleoyl phosphatidylcholine, with and without 33% cholesterol, and relaxation times were measured. Peptide concentration ranged from 0. 5 to 10 mol %. The peptide behaved as predominant monomers undergoing rapid symmetric rotational diffusion; however, there was evidence of reversible side-to-side interaction among the hydrophobic transmembrane domains, particularly at physiological temperatures and in the presence of natural concentrations of cholesterol. The results of these experiments in fluid membranes are consistent with the existence of lipid-protein interactions that would predispose to receptor microdomain formation in membranes of higher animal cells. 相似文献
72.
Melissa M.B. Morrow Wendy J. Hurd Kenton R. Kaufman Kai-Nan An 《Journal of electromyography and kinesiology》2010,20(1):61-67
ObjectiveInvestigate shoulder joint kinetics over a range of daily activity and mobility tasks associated with manual wheelchair propulsion to characterize demands placed on the shoulder during the daily activity of manual wheelchair users.DesignCase series.SubjectsTwelve individuals who were experienced manual wheelchair users.MethodsUpper extremity kinematics and handrim wheelchair kinetics were measured over level propulsion, ramp propulsion, start and stop over level terrain, and a weight relief maneuver. Shoulder intersegmental forces and moments were calculated from inverse dynamics for all conditions.ResultsWeight relief resulted in significantly higher forces and ramp propulsion resulted in significantly higher moments than the other conditions. Surprisingly, the start condition resulted in large intersegmental moments about the shoulder equivalent with that of the ramp propulsion, while the demand imparted by the stop condition was shown to be equivalent to level propulsion across all forces and moments.ConclusionsThis study provides characterization of daily living and mobility activities associated with manual wheelchair propulsion not previously reported and identifies activities that result in higher shoulder kinetics when compared to standard level propulsion. 相似文献
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Craig Jamieson Robert A. Campbell Iain A. Cumming Kevin J. Gillen Jonathan Gillespie Bert Kazemier Michael Kiczun Yvonne Lamont Amanda J. Lyons John K.F. Maclean Frederic Martin Elizabeth M. Moir John A. Morrow John Pantling Zoran Rankovic Lynn Smith 《Bioorganic & medicinal chemistry letters》2010,20(20):6072-6075
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity. 相似文献
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Kimberly G. Norman Jeffrey A. Canter Mingjian Shi Ginger L. Milne Jason D. Morrow James E. Sligh 《Mitochondrion》2010,10(2):94-101
Transplant recipients have an elevated risk of skin cancer, with a 65- to 250-fold increase in squamous cell carcinoma. Usage of the immunosuppressant cyclosporine A (CsA) is associated with the development of skin cancer. We hypothesized that the increased incidence of skin cancer was due to the action of CsA within keratinocyte mitochondria where it can inhibit mitochondrial permeability transition pore (MPTP) opening. Normally, MPTP opening is induced by oxidative stress such as that caused by UV light and leads to cell death, thereby eliminating a cell that has been exposed to genotoxic insult. However, in the presence of CsA, damaged cells may survive and consequently form tumors. To test this hypothesis, we treated keratinocytes with levels of CsA used therapeutically in transplant patients and assessed their viability following UVA-irradiation. CsA prevented cell death by inhibiting MPTP opening, even though the levels of oxidative stress were increased markedly. Nim811, a non-immunosuppressive drug that can block the MPTP had a similar effect while the immunosuppressive drug tacrolimus that does not interact with the mitochondria had no effect. These findings suggest that CsA may promote skin cancer in transplant patients by allowing keratinocyte survival under conditions of increased genotoxic stress. 相似文献
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We have used V79MZ hamster lung fibroblasts stably transfected with human cytochrome P450-1A1 (hCYP1A1; cell line designated V79MZh1A1) or P450-1B1 (hCYP1B1; cell line designated V79MZh1B1) alone, or in combination with human glutathione-S-transferase (GST) alpha-1 (hGSTA1), in order to examine GST protection against cytotoxicity and mutagenicity of dibenzo[a,l]pyrene (DBP) and the intermediate dihydrodiol metabolite (+/-)-DBP-11,12-dihydrodiol (DBPD). At comparable expression levels of hCYP1A1 and hCYP1B1, both DBP and DBPD were more cytotoxic in V79MZ1A1 (IC(50)=2.7 and 0.7nM, respectively) than in V79MZh1B1 (IC(50)=6.0 and 4.8nM, respectively). In contrast, both DBP and DBPD were two- to four-fold more mutagenic in V79MZh1B1 than in V79MZ1A1. Co-expression of hGSTA1 with hCYP1A1 decreased DBP cytotoxicity two-fold compared to V79MZh1A1 with hCYP1A1 alone, and provided a small, yet still statistically significant, 1.3-fold protection against DBPD. Protection against mutagenicity of these compounds was comparable to that for cytotoxicity in cells expressing hCYP1A1. In V79MZh1B1 cells, co-expression of hGSTA1 conferred up to five-fold protection against DBP cytotoxicity, and up to nine-fold protection against the (+/-)-DBP-dihydrodiol cytotoxicity relative to the cells expressing hCYP1B1 alone. Co-expression of hGSTA1 also reduced mutagenicity of DBP or its dihydrodiol to a lesser extent (1.3-1.8-fold) than the protection against cytotoxicity in cells expressing hCYP1B1. These findings demonstrate that the protective efficacy of hGSTA1 against DBP and DBPD toxicity is variable, depending on the compound or metabolite present, the specific cytochrome P450 isozyme expressed, and the specific cellular damage endpoint examined. 相似文献
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Jin J Wang Y Wang F Kerns JK Vinader VM Hancock AP Lindon MJ Stevenson GI Morrow DM Rao P Nguyen C Barrett VJ Browning C Hartmann G Andrew DP Sarau HM Foley JJ Jurewicz AJ Fornwald JA Harker AJ Moore ML Rivero RA Belmonte KE Connor HE 《Bioorganic & medicinal chemistry letters》2007,17(6):1722-1725
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described. 相似文献
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