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91.
Arhamatoulaye Ma?ga Jon Merlin Elodie Marcon Céline Rouget Maud Larregola Bernard Gilquin Carole Fruchart-Gaillard Evelyne Lajeunesse Charles Marchetti Alain Lorphelin Laurent Bellanger Roger J. Summers Dana S. Hutchinson Bronwyn A. Evans Denis Servent Nicolas Gilles 《PloS one》2013,8(7)
ρ-Da1a is a three-finger fold toxin from green mamba venom that is highly selective for the α1A-adrenoceptor. This toxin has atypical pharmacological properties, including incomplete inhibition of 3H-prazosin or 125I-HEAT binding and insurmountable antagonist action. We aimed to clarify its mode of action at the α1A-adrenoceptor. The affinity (pKi 9.26) and selectivity of ρ-Da1a for the α1A-adrenoceptor were confirmed by comparing binding to human adrenoceptors expressed in eukaryotic cells. Equilibrium and kinetic binding experiments were used to demonstrate that ρ-Da1a, prazosin and HEAT compete at the α1A-adrenoceptor. ρ-Da1a did not affect the dissociation kinetics of 3H-prazosin or 125I-HEAT, and the IC50 of ρ-Da1a, determined by competition experiments, increased linearly with the concentration of radioligands used, while the residual binding by ρ-Da1a remained stable. The effect of ρ-Da1a on agonist-stimulated Ca2+ release was insurmountable in the presence of phenethylamine- or imidazoline-type agonists. Ten mutations in the orthosteric binding pocket of the α1A-adrenoceptor were evaluated for alterations in ρ-Da1a affinity. The D1063.32A and the S1885.42A/S1925.46A receptor mutations reduced toxin affinity moderately (6 and 7.6 times, respectively), while the F862.64A, F2886.51A and F3127.39A mutations diminished it dramatically by 18- to 93-fold. In addition, residue F862.64 was identified as a key interaction point for 125I-HEAT, as the variant F862.64A induced a 23-fold reduction in HEAT affinity. Unlike the M1 muscarinic acetylcholine receptor toxin MT7, ρ-Da1a interacts with the human α1A-adrenoceptor orthosteric pocket and shares receptor interaction points with antagonist (F862.64, F2886.51 and F3127.39) and agonist (F2886.51 and F3127.39) ligands. Its selectivity for the α1A-adrenoceptor may result, at least partly, from its interaction with the residue F862.64, which appears to be important also for HEAT binding. 相似文献
92.
93.
P. G. Wyatt A. S. Anslow B. A. Coomber R. P.C. Cousins D. N. Evans V. S. Gilbert 《Nucleosides, nucleotides & nucleic acids》2013,32(9-10):2039-2049
Abstract A short high yielding synthesis of the potent anti-varicella-zoster virus (VZV) carbocyclic nucleoside analogue carba-BVDU 1 starting from aminodiol 2 is described. Reaction of 2 with acyl carbamate 3 and subsequent ring closure under acidic conditions afforded 5-ethyl-2′-deoxy-4′a-carbauridine 5. In situ acetylation of 5 afforded 3′,5′-di-O-acetyl-5-ethyl-2′-deoxy-4′a-carbauridine 6 in 78% overall yield from 2. Radical bromination of 6 with either bromine or NBS and subsequent treatment with triethylamine gave an efficient conversion to 3′,5′-di-O-acetyl-5-(E)-(2-bromovinyl)-2′-deoxy-4′a-carbauridine 7. Deacetylation of 7 afforded 1 in an overall 45–53% yield from 2. 相似文献
94.
Mammalian carbamyl phosphate synthetase (CPS). DNA sequence and evolution of the CPS domain of the Syrian hamster multifunctional protein CAD 总被引:2,自引:0,他引:2
J P Simmer R E Kelly A G Rinker J L Scully D R Evans 《The Journal of biological chemistry》1990,265(18):10395-10402
Glutamine-dependent carbamoyl-phosphate synthetase (EC 6.3.5.5) catalyzes the first step in de novo pyrimidine biosynthesis. The mammalian enzyme is part of a 240-kDa multifunctional protein which also has the second (aspartate carbamoyltransferase, EC 2.1.3.2), and third (dihydroorotase, EC 3.5.2.3) activities of the pathway. Shigesada et al. (Shigesada, K., Stark, G.R., Maley, J.A., and Davidson, J.N. (1985) Mol. Cell Biol. 175, 1-7) produced a truncated cDNA clone from a Syrian hamster cell line that contained most of the coding region for this protein. We have completed sequencing this clone, known as pCAD142. The cDNA insert contained all of the coding region for the glutaminase (GLN) and carbamyl phosphate synthetase (CPS) domains but lacked a short amino-terminal segment. By comparing the primary structure of the mammalian chimera to monofunctional proteins we have identified the borders of the functional domains. The GLN domain is 21 kDa, close to the size of the functionally similar polypeptide products of the Escherichia coli pabA and hisH genes. The domain has the three regions of homology common to trpG-type glutamine amidotransferases, as well as a fourth region specific to the carbamyl phosphate synthetases. The CPSase domain is similar to other reported CPSases in size (120 kDa), primary structure (37-67% amino acid identity), and homology between its amino and carboxyl halves. Analysis of the nucleotide and amino acid sequence identities among the various carbamyl phosphate synthetases suggests that the gene fusion which joined the GLN and CPS domains was an early event in the evolution of eukaryotic organisms and that the Saccharomyces cerevisiae enzyme consisting of separate subunits arose by defusion from an ancestral multifunctional protein. 相似文献
95.
Biomechanical and morphometric comparisons among coleoptilesfrom wheat seedlings differing in Rht gene-dosage (Rht = 0,2, 4 doses) are presented in an effort to evaluate the influenceof Rht on the mechanics of soil penetration by this organ. Rhtis known to reduce seedling establishment compared to the wildtype. Data from 37-day-old seedlings indicate that Rhtreduces tissue elastic modulus E, increases the second momentof area I, and decreases the slenderness ratio (l/r) of coleoptiles.Rht-relatedchanges in E and I are such that the flexural stiffness of coleoptilesfrom Rht plants does not differ significantly from the wildtype-hence the growing coleoptiles of all three genotypes haveequivalent biomechanical capacity to penetrate the soil. Rhtreduction of coleoptile slenderness ratios confers a capacityto safely sustain higher axial compressive loads compared tocoleoptiles with equivalent flexural stiffness but higher ratios.However, wild type seedlings produce longer coleoptiles andlonger subcrown internodes than Rht seedlings. Longer coleoptilesdeliver the crown node closer to the top of the soil beforethe crown node extends beyond the lateral confinement of thecoleoptile. This reduces the potential for buckling of the subcrowninternode and leaves due to the compressive loading of soil.Rht affects a variety of mechanical features whose influenceis dependent upon the stage of seedling growth and the degreeof soil compaction. However, at equivalent depths of burialwhich exceed the maximum length of coleoptiles and moderatesoil compaction, Rht is biomechanically disadvantageous to seedlingestablishment. Wheat, germination, biomechanics, Rht-gene 相似文献
96.
97.
In a survey of antagonists of nematodes in 27 citrus groves, each with a history of Tylenchulus semipenetrans infestation, and 17 noncitrus habitats in Florida, approximately 24 species of microbial antagonists capable of attacking vermiform stages of Radopholus citrophilus were recovered. Eleven of these microbes and a species of Pasteuria also were observed attacking vermiform stages of T. semipenetrans. Verticillium chlamydosporium, Paecilomyces lilacinus, P. marquandii, Streptomyces sp., Arthrobotrys oligospora, and Dactylella ellipsospora were found infecting T. semipenetrans egg masses. Two species of nematophagous amoebae, five species of predatory nematodes, and 29 species of nematophagous arthropods also were detected. Nematode-trapping fungi and nematophagous arthropods were common inhabitants of citrus groves with a history of citrus nematode infestation; however, obligate parasites of nematodes were rare. 相似文献
98.
99.
100.
Huw I. Griffiths Erika Pietrzeniuk Roland Fuhrmann Jack J. Lennon Koen Martens John G. Evans 《Journal of Biogeography》1998,25(3):515-526
Abstract. The freshwater ostracod Tonnacypris glacialis (Sars, 1890) is reported from the European Pleistocene for the first time. The historical allocation of the species is discussed, and the species composition and characteristics of Tonnacypris Diebel & Pietrzeniuk (1975) and its phylozoogeography are considered. The significance of T. glacialis is reviewed, particularly from the viewpoint of the possible implications of parthenogenesis (and occasional-male production) for the Quaternary history of the genus, and for the use of the species in palaeoenvironmental reconstruction. It is suggested that the Pleistocene fossil occurrence of T. glacialis in modern temperature latitudes is a robust indicator of mean summer temperatures of 6°C. 相似文献