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991.
The structural basis of lipid acyl-chain selection by membrane-intrinsic enzymes is poorly understood because most integral membrane enzymes of lipid metabolism have proven refractory to structure determination; however, robust enzymes from the outer membranes of gram-negative bacteria are now providing a first glimpse at the underlying mechanisms. The methylene unit resolution of the phospholipid:lipid A palmitoyltransferase PagP is determined by the hydrocarbon ruler, a 16-carbon saturated acyl-chain-binding pocket buried within the transmembrane beta-barrel structure. Substitution of Gly88 lining the floor of the hydrocarbon ruler with Ala or Met makes the enzyme select specifically 15- or 12-carbon saturated acyl chains, respectively, indicating that hydrocarbon ruler depth determines acyl-chain selection. However, the Gly88Cys PagP resolution does not diminish linearly because it selects both 14- and 15-carbon saturated acyl chains. We discovered that an exciton, emanating from a buried Tyr26-Trp66 phenol-indole interaction, is extinguished by a local structural perturbation arising from the proximal Gly88Cys PagP sulfhydryl group. Site-specific S-methylation of the single Cys afforded Gly88Cys-S-methyl PagP, which reasserted both the exciton and methylene unit resolution by specifically selecting 13-carbon saturated acyl chains for transfer to lipid A. Unlike the other Gly88 substitutions, the Cys sulfhydryl group recedes from the hydrocarbon ruler floor and locally perturbs the subjacent Tyr26 and Trp66 aromatic rings. The resulting hydrocarbon ruler expansion thus occurs at the exciton's expense and accommodates an extra methylene unit in the selected acyl chain. The hydrocarbon ruler-exciton juxtaposition endows PagP with a molecular gauge for probing the structural basis of lipid acyl-chain selection in a membrane-intrinsic environment. 相似文献
992.
Edwin C. Constable Catherine E. Housecroft Markus Neuburger Silvia Schaffner Ellen J. Shardlow 《Inorganica chimica acta》2007,360(15):4069-4076
The heteroditopic ligand 4′-(4,7,10-trioxadec-1-yn-10-yl)-2,2′:6′,2″-terpyridine, 2, contains an N,N′,N″-donor metal-binding domain that recognizes iron(II), and a terminal alkyne site that selectively couples to platinum(II). This selectivity has been used to investigate routes to the formation of heterometallic systems. The single crystal structures of ligand 2 and the complex [Fe(2)2][PF6]2 are reported. 相似文献
993.
Stein CM Zalwango S Chiunda AB Millard C Leontiev DV Horvath AL Cartier KC Chervenak K Boom WH Elston RC Mugerwa RD Whalen CC Iyengar SK 《Human genetics》2007,121(6):663-673
Tuberculosis (TB) is a growing public health threat globally and several studies suggest a role of host genetic susceptibility
in increased TB risk. As part of a household contact study in Kampala, Uganda, we have taken a unique approach to the study
of genetic susceptibility to TB by developing an intermediate phenotype model for TB susceptibility, analyzing levels of tumor
necrosis factor-α (TNFα) in response to culture filtrate as the phenotype. In the present study, we analyzed candidate genes
related to TNFα regulation and found that interleukin (IL)-10, interferon-gamma receptor 1 (IFNGR1), and TNFα receptor 1 (TNFR1) genes were linked and associated to both TB and TNFα. We also show that these associations are with progression to active
disease and not susceptibility to latent infection. This is the first report of an association between TB and TNFR1 in a human population and our findings for IL-10 and IFNGR1 replicate previous findings. By observing pleiotropic effects on both phenotypes, we show construct validity of our intermediate
phenotype model, which enables the characterization of the role of these genetic polymorphisms on TB pathogenesis. This study
further illustrates the utility of such a model for disentangling complex traits.
C. C. Whalen and S. K. Iyengar contributed equally as senior authors of this work. 相似文献
994.
Wang C Bomberg E Billington C Levine A Kotz CM 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,293(3):R1003-R1012
Recent studies show that brain-derived neurotrophic factor (BDNF) decreases feeding and body weight after peripheral and ventricular administration. BDNF mRNA and protein, and its receptor tyrosine kinase B (TrkB) are widely distributed in the hypothalamus and other brain regions. However, there are few reports on specific brain sites of actions for BDNF. We evaluated the effect of BDNF in the hypothalamic paraventricular nucleus (PVN) on feeding. BDNF injected unilaterally or bilaterally into the PVN of food-deprived and nondeprived rats significantly decreased feeding and body weight gain within the 0- to 24-h and 24- to 48-h postinjection intervals. Effective doses producing inhibition of feeding behavior did not establish a conditioned taste aversion. PVN BDNF significantly decreased PVN neuropeptide Y (NPY)-induced feeding at 1, 2, and 4 h following injection. BDNF administration in the PVN abolished food-restriction-induced NPY gene expression in the hypothalamic arcuate nucleus. In conclusion, BDNF in the PVN significantly decreases food intake and body weight gain, suggesting that the PVN is an important site of action for BDNF in its effects on energy metabolism. Furthermore, BDNF appears to interact with NPY in its anorectic actions, although a direct effect on NPY remains to be established. 相似文献
995.
Rakusan K Chvojkova Z Oliviero P Ostadalova I Kolar F Chassagne C Samuel JL Ostadal B 《American journal of physiology. Heart and circulatory physiology》2007,292(3):H1237-H1244
Chronic hypoxia has been shown to stimulate myocardial microvascular growth and improve cardiac ischemic tolerance in young and adult rats. The aim of this study was to determine whether the ANG II type 1 receptor (AT(1)) pathway was involved in these processes. Newborn Wistar rats, exposed to chronic intermittent hypoxia (8 h/day) for 10 days, were simultaneously treated with AT(1) receptor blocker irbesartan and compared with untreated animals. The major finding is that chronic hypoxia increased the capillary supply of myocardial tissue, which was even more pronounced in hypertrophied right ventricle, whereas increased arteriolar supply was found only in the left ventricle. This angiogenic response was completely prevented by irbesartan. Moreover, chronic hypoxia improved the postischemic recovery of cardiac contractile function during reperfusion, and this protective effect was also completely abolished by irbesartan. Chronic hypoxia increased the myocardial density of AT(1) but not of ANG II type 2 receptor subtypes, whereas the effect of irbesartan was not significant. The expression of caveolin-1alpha markedly increased in response to chronic hypoxia, and irbesartan prevented this effect. Neither hypoxia nor irbesartan treatment altered the expression of nitric oxide synthase 3, heat shock protein 90, and VEGF. It is concluded that the AT(1) receptor pathway plays an important role in coronary angiogenesis and improved cardiac ischemic tolerance induced in neonatal rats by chronic hypoxia. 相似文献
996.
997.
Cd36, a class B scavenger receptor, functions as a monomer to bind acetylated and oxidized low-density lipoproteins 总被引:1,自引:0,他引:1
Martin CA Longman E Wooding C Hoosdally SJ Ali S Aitman TJ Gutmann DA Freemont PS Byrne B Linton KJ 《Protein science : a publication of the Protein Society》2007,16(11):2531-2541
Cd36 is a small-molecular-weight integral membrane protein expressed in a diverse, but select, range of cell types. It has an equally diverse range of ligands and physiological functions, which has implicated Cd36 in a number of diseases including insulin resistance, diabetes, and, most notably, atherosclerosis. The protein is reported to reside in detergent-resistant microdomains within the plasma membrane and to form homo- and hetero-intermolecular interactions. These data suggest that this class B scavenger receptor may gain functionality for ligand binding, and/or ligand internalization, by formation of protein complexes at the cell surface. Here, we have overexpressed Cd36 in insect cells, purified the recombinant protein to homogeneity, and analyzed its stability and solubility in a variety of nonionic and zwitterionic detergents. Octylglucoside conferred the greatest degree of stability, and by analytical ultracentrifugation we show that the protein is monomeric. A solid-phase ligand-binding assay demonstrated that the purified monomeric protein retains high affinity for acetylated and oxidized low-density lipoproteins. Therefore, no accessory proteins are required for interaction with ligand, and binding is a property of the monomeric fold of the protein. Thus, the highly purified and functional Cd36 should be suitable for crystallization in octylglucoside, and the in vitro ligand-binding assay represents a promising screen for identification of bioactive molecules targeting atherogenesis at the level of ligand binding. 相似文献
998.
Larsen SD Poel TJ Filipski KJ Kohrt JT Pfefferkorn JA Sorenson RJ Tait BD Askew V Dillon L Hanselman JC Lu GH Robertson A Sekerke C Kowala MC Auerbach BJ 《Bioorganic & medicinal chemistry letters》2007,17(20):5567-5572
An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity. 相似文献
999.
Coutu C Brandle J Brown D Brown K Miki B Simmonds J Hegedus DD 《Transgenic research》2007,16(6):771-781
We present a series of 14 binary vectors suitable for Agrobacterium-mediated transformation of dicotyledonous plants and adaptable for biolistic transformation of monocotyledonous plants. The
vector size has been minimized by eliminating all non-essential elements from the vector backbone and T-DNA regions while
maintaining the ability to replicate independently. The smallest of the vector series is 6.3 kb and possesses an extensive
multiple cloning site with 21 unique restriction endonuclease sites that are compatible with common cloning, protein expression,
yeast two-hybrid and other binary vectors. The T-DNA region was engineered using a synthetic designer oligonucleotide resulting
in an entirely modular system whereby any vector element can be independently exchanged. The high copy number ColE1 origin
of replication has been included to enhance plasmid yield in Escherichia coli. FRT recombination sites flank the selectable marker cassette regions and allow for in planta excision by FLP recombinase. The pORE series consists of three basic types; an ‘open’ set for general plant transformation, a ‘reporter’ set for promoter analysis and an ‘expression’ set for constitutive expression of transgenes. The sets comprise various combinations of promoters (P
HPL, P
ENTCUP2 and P
TAPADH), selectable markers (nptII and pat) and reporter genes (gusA and smgfp). 相似文献
1000.
Barclay WS Jones IM Osborn HM Phillipson L Ren J Talevera GA Thompson CI 《Bioorganic & medicinal chemistry》2007,15(12):4038-4047
Influenza viruses attach to host cells by binding to terminal sialic acid (Neu5Ac) on glycoproteins or glycolipids. Both the linkage of Neu5Ac and the identity of other carbohydrates within the oligosaccharide are thought to play roles in restricting the host range of the virus. In this study, the receptor specificity of an H5 avian influenza virus haemagglutinin protein that has recently infected man (influenza strain A/Vietnam/1194/04) has been probed using carbohydrate functionalised poly(acrylic acid) polymers. A baculovirus expression system that allows facile and safe analysis of the Neu5Ac binding specificity of mutants of H5 HA engineered at sites that are predicted to effect a switch in host range has also been developed. 相似文献