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81.
Mareuil F Sizun C Perez J Schoenauer M Lallemand JY Bontems F 《European biophysics journal : EBJ》2007,37(1):95-104
Most proteins comprise several domains and/or participate in functional complexes. Owing to ongoing structural genomic projects,
it is likely that it will soon be possible to predict, with reasonable accuracy, the conserved regions of most structural
domains. Under these circumstances, it will be important to have methods, based on simple-to-acquire experimental data, that
allow to build and refine structures of multi-domain proteins or of protein complexes from homology models of the individual
domains/proteins. It has been recently shown that small angle X-ray scattering (SAXS) and NMR residual dipolar coupling (RDC)
data can be combined to determine the architecture of such objects when the X-ray structures of the domains are known and
can be considered as rigid objects. We developed a simple genetic algorithm to achieve the same goal, but by using homology
models of the domains considered as deformable objects. We applied it to two model systems, an S1KH bi-domain of the NusA
protein and the γS-crystallin protein. Despite its simplicity our algorithm is able to generate good solutions when driven
by SAXS and RDC data. 相似文献
82.
Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance
Flowers JB Oler AT Nadler ST Choi Y Schueler KL Yandell BS Kendziorski CM Attie AD 《American journal of physiology. Endocrinology and metabolism》2007,292(3):E936-E945
Insulin resistance is a common feature of obesity. BTBR mice have more fat mass than most other inbred mouse strains. On a chow diet, BTBR mice have elevated insulin levels relative to the C57BL/6J (B6) strain. Male F1 progeny of a B6 x BTBR cross are insulin resistant. Previously, we reported insulin resistance in isolated muscle and in isolated adipocytes in this strain. Whereas the muscle insulin resistance was observed only in male F1 mice, adipocyte insulin resistance was also present in male BTBR mice. We examined in vivo mechanisms of insulin resistance with the hyperinsulinemic euglycemic clamp technique. At 10 wk of age, BTBR and F1 mice had a >30% reduction in whole body glucose disposal primarily due to insulin resistance in heart, soleus muscle, and adipose tissue. The increased adipose tissue mass and decreased muscle mass in BTBR and F1 mice were negatively and positively correlated with whole body glucose disposal, respectively. Genes involved in focal adhesion, actin cytoskeleton, and inflammation were more highly expressed in BTBR and F1 than in B6 adipose tissue. The BTBR and F1 mice have higher levels of testosterone, which may be related to the pathological changes in adipose tissue that lead to systemic insulin resistance. Despite profound peripheral insulin resistance, BTBR and F1 mice retained hepatic insulin sensitivity. These studies reveal a genetic difference in body composition that correlates with large differences in peripheral insulin sensitivity. 相似文献
83.
84.
Kubrusly RC Ventura AL de Melo Reis RA Serra GC Yamasaki EN Gardino PF de Mello MC de Mello FG 《Neurochemistry international》2007,50(1):211-218
Dopamine is the main catecholamine found in the chick retina whereas norepinephrine is only found in trace amounts. We compared the effectiveness of dopamine and norepinephrine in promoting cyclic AMP accumulation in retinas at embryonic day 13 (E13) and from post-hatched chicken (P15). Dopamine (EC(50)=10microM) and norepinephrine (EC(50)=30microM), but not the beta(1)-adrenergic agonist isoproterenol, stimulated over seven-fold the production of cyclic AMP in E13 retina. The cyclic AMP accumulation induced by both catecholamines in embryonic tissue was entirely blocked by 2microM SCH23390, a D(1) receptor antagonist, but not by alprenolol (beta-adrenoceptor antagonist). In P15 retinas, 100microM isoproterenol stimulated five-fold the accumulation of cAMP. This effect was blocked by propanolol (10microM), but not by 2microM SCH23390. Embryonic and adult retina display beta(1) adrenergic receptor mRNA as detected by RT-PCR, but the beta(1) adrenergic receptor protein was detected only in post-hatched tissue. We conclude that norepinephrine cross-reacts with D(1) dopaminergic receptor with affinity similar to that of dopamine in the embryonic retina. In the mature retina, however, D(1) receptors become restricted to activation by dopamine. Moreover, as opposed to the embryonic tissue, norepinephrine seems to stimulate cAMP accumulation via beta(1)-like adrenergic receptors in the mature tissue. 相似文献
85.
86.
Kurth I Thompson DA Rüther K Feathers KL Chrispell JD Schroth J McHenry CL Schweizer M Skosyrski S Gal A Hübner CA 《Molecular and cellular biology》2007,27(4):1370-1379
RDH12 codes for a member of the family of short-chain alcohol dehydrogenases/reductases proposed to function in the visual cycle that supplies the chromophore 11-cis retinal to photoreceptor cells. Mutations in RDH12 cause severe and progressive childhood onset autosomal-recessive retinal dystrophy, including Leber congenital amaurosis. We generated Rdh12 knockout mice, which exhibited grossly normal retinal histology at 10 months of age. Levels of all-trans and 11-cis retinoids in dark- and light-adapted animals and scotopic and photopic electroretinogram (ERG) responses were similar to those for the wild type, as was recovery of the ERG response following bleaching, for animals matched for an Rpe65 polymorphism (p.L450M). Lipid peroxidation products and other measures of oxidative stress did not appear to be elevated in Rdh12(-/-) animals. RDH12 was localized to photoreceptor inner segments and the outer nuclear layer in both mouse and human retinas by immunohistochemistry. The present findings, together with those of earlier studies showing only minor functional deficits in mice deficient for Rdh5, Rdh8, or Rdh11, suggest that the activity of any one isoform is not rate limiting in the visual response. 相似文献
87.
Kuduk SD DiPardo RM Chang RK Di Marco CN Murphy KL Ransom RW Reiss DR Tang C Prueksaritanont T Pettibone DJ Bock MG 《Bioorganic & medicinal chemistry letters》2007,17(13):3608-3612
SAR study of the biphenyl region of cyclopropanecarboxamide derived bradykinin B(1) antagonists was examined. Incorporation of a pyridine in place of the proximal phenyl ring and chlorination of the distal phenyl ring proved to be well tolerated and provided compounds with improved pharmacokinetic profiles, CNS penetration, and enhanced receptor occupancy. 相似文献
88.
Luft JR Wolfley JR Said MI Nagel RM Lauricella AM Smith JL Thayer MH Veatch CK Snell EH Malkowski MG Detitta GT 《Protein science : a publication of the Protein Society》2007,16(4):715-722
An efficient optimization method for the crystallization of biological macromolecules has been developed and tested. This builds on a successful high-throughput technique for the determination of initial crystallization conditions. The optimization method takes an initial condition identified through screening and then varies the concentration of the macromolecule, precipitant, and the growth temperature in a systematic manner. The amount of sample and number of steps is minimized and no biochemical reformulation is required. In the current application a robotic liquid handling system enables high-throughput use, but the technique can easily be adapted in a nonautomated setting. This method has been applied successfully for the rapid optimization of crystallization conditions in nine representative cases. 相似文献
89.
Martin MW Newcomb J Nunes JJ Bemis JE McGowan DC White RD Buchanan JL DiMauro EF Boucher C Faust T Hsieh F Huang X Lee JH Schneider S Turci SM Zhu X 《Bioorganic & medicinal chemistry letters》2007,17(8):2299-2304
2,3-Diarylfuro[2,3-b]pyridine-4-amines are a novel class of potent and selective inhibitors of Lck. The discovery, synthesis, and structure activity relationships of this series of inhibitors are reported. The most promising compounds were also profiled to deduce their pharmacokinetic properties. 相似文献
90.
Duarte FS Codeço Martins PR Romeiro GA Monteiro De Lima TC 《Bioorganic & medicinal chemistry》2007,15(4):1645-1650
This study investigated the antidepressant-like effect of 4-amine derivatives of 10,11-dihydro-5H-dibenzo-alkylamine-cycloheptane, 4-amine (3-N,N-dimethylpropylamine)-10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5-one (ADDCH1) and 1,2,3,4,8,9-hexahydro-dibenzocyclohepta[4,4a,5-ef]1,4-diazepin (ADDCH2), in a validated experimental model of depression, the forced swimming test (FST) in mice. Female adult mice were sub-chronically (three doses in 24 h) or repeatedly (once a day for 10 days) treated with either of the compounds and evaluated in the FST. The sub-chronic treatment promoted a dose-dependent reduction in the immobility time in the FST with the doses of 50 mg/kg (ADDCH1) and 30 mg/kg (ADDCH2) ip being the most effective (33% and 37% of reduction, respectively). A similar profile of action was observed in the animals repeatedly treated with ADDCH1 50 mg/kg or ADDCH2 30 mg/kg ip (for 10 days) and there was no sign of motor impairment or locomotor activation as evaluated in the rota-rod and open-field tests, respectively. These findings suggest that these amine derivatives of the system dibenzocycloheptane have an antidepressant-like action which could be of clinical interest and, therefore, deserves further investigation. In addition, putative underlying mechanisms of action are discussed. 相似文献