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排序方式: 共有110条查询结果,搜索用时 312 毫秒
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Shimamura T Shiroishi M Weyand S Tsujimoto H Winter G Katritch V Abagyan R Cherezov V Liu W Han GW Kobayashi T Stevens RC Iwata S 《Nature》2011,475(7354):65-70
The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp?428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys?191(5.39) and/or Lys?179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R. 相似文献
3.
Greenway MJ Andersen PM Russ C Ennis S Cashman S Donaghy C Patterson V Swingler R Kieran D Prehn J Morrison KE Green A Acharya KR Brown RH Hardiman O 《Nature genetics》2006,38(4):411-413
We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration. 相似文献
4.
Maria Pasztoi Agnes Bonifacius Joern Pezoldt Devesha Kulkarni Jana Niemz Juhao Yang René Teich Janina Hajek Fabio Pisano Manfred Rohde Petra Dersch Jochen Huehn 《Cellular and molecular life sciences : CMLS》2017,74(15):2839-2850
Adaptive immunity critically contributes to control acute infection with enteropathogenic Yersinia pseudotuberculosis; however, the role of CD4+ T cell subsets in establishing infection and allowing pathogen persistence remains elusive. Here, we assessed the modulatory capacity of Y. pseudotuberculosis on CD4+ T cell differentiation. Using in vivo assays, we report that infection with Y. pseudotuberculosis resulted in enhanced priming of IL-17-producing T cells (Th17 cells), whereas induction of Foxp3+ regulatory T cells (Tregs) was severely disrupted in gut-draining mesenteric lymph nodes (mLNs), in line with altered frequencies of tolerogenic and proinflammatory dendritic cell (DC) subsets within mLNs. Additionally, by using a DC-free in vitro system, we could demonstrate that Y. pseudotuberculosis can directly modulate T cell receptor (TCR) downstream signaling within naïve CD4+ T cells and Tregs via injection of effector molecules through the type III secretion system, thereby affecting their functional properties. Importantly, modulation of naïve CD4+ T cells by Y. pseudotuberculosis resulted in an enhanced Th17 differentiation and decreased induction of Foxp3+ Tregs in vitro. These findings shed light to the adjustment of the Th17-Treg axis in response to acute Y. pseudotuberculosis infection and highlight the direct modulation of CD4+ T cell subsets by altering their TCR downstream signaling. 相似文献
5.
Lifestyle transitions in plant pathogenic Colletotrichum fungi deciphered by genome and transcriptome analyses 总被引:8,自引:0,他引:8
RJ O'Connell MR Thon S Hacquard SG Amyotte J Kleemann MF Torres U Damm EA Buiate L Epstein N Alkan J Altmüller L Alvarado-Balderrama CA Bauser C Becker BW Birren Z Chen J Choi JA Crouch JP Duvick MA Farman P Gan D Heiman B Henrissat RJ Howard M Kabbage C Koch B Kracher Y Kubo AD Law MH Lebrun YH Lee I Miyara N Moore U Neumann K Nordström DG Panaccione R Panstruga M Place RH Proctor D Prusky G Rech R Reinhardt JA Rollins S Rounsley CL Schardl DC Schwartz N Shenoy K Shirasu UR Sikhakolli K Stüber 《Nature genetics》2012,44(9):1060-1065
6.
Jochen Althoff 《Studies in history and philosophy of science》2012,43(2):293-299
This paper explores the differences between poetry and prose in philosophical writing by examining two Pre-Socratic fragments, one in verse and one in prose, that express a very similar thought: Empedocles 59 B 17 Diels/Kranz and Anaxagoras 31 B 8 D./K. Although at first it might seem as though there is a simple division between Empedocles’ opaque and allusive hexameters and Anaxagoras’ sober prose, when we look in detail at the language used by the two authors, a close reading of the passages reveals a more complex picture. Both authors place rhetorical emphasis on their own role as innovator; Anaxagoras’ prose shows a careful attention to style and word choice no less than Empedocles’ poetry, and Empedocles’ poetry itself reflects the range of stylistic registers and types of material that hexameter could be used for in antiquity. There is no simple antithesis between prose style and hexametric poetry, and the words and stylistic devices an author chooses are constitutive of the thought he expresses. 相似文献
7.
K. Silberbauer H. Sinzinger Maya Winter W. Feigl F. Ring 《Cellular and molecular life sciences : CMLS》1978,34(11):1471-1472
Summary Morphological control of Moncada's bioassay for prostacyclin (PG I2) activity measurement shows that the activity depends not only on endothelium, but in important amounts on subendothelial tissue too. Therefore, it can be concluded that platelet thrombus formation after endothelial cell injury does not depend only on the PG I2-producing ability of the tissue. 相似文献
8.
The molybdenum cofactor is part of the active site of all molybdenum-dependent enzymes, except nitrogenase. The molybdenum cofactor consists of molybdopterin, a phosphorylated pyranopterin, with an ene-dithiolate coordinating molybdenum. The same pyranopterin-based cofactor is involved in metal coordination of the homologous tungsten-containing enzymes found in archea. The molybdenum cofactor is synthesized by a highly conserved biosynthetic pathway. In plants, the multidomain protein Cnx1 catalyses the insertion of molybdenum into molybdopterin. The Cnx1 G domain (Cnx1G), whose crystal structure has been determined in its apo form, binds molybdopterin with high affinity and participates in the catalysis of molybdenum insertion. Here we present two high-resolution crystal structures of Cnx1G in complex with molybdopterin and with adenylated molybdopterin (molybdopterin-AMP), a mechanistically important intermediate. Molybdopterin-AMP is the reaction product of Cnx1G and is subsequently processed in a magnesium-dependent reaction by the amino-terminal E domain of Cnx1 to yield active molybdenum cofactor. The unexpected identification of copper bound to the molybdopterin dithiolate sulphurs in both structures, coupled with the observed copper inhibition of Cnx1G activity, provides a molecular link between molybdenum and copper metabolism. 相似文献
9.
Sex differences in gonadotrophin concentrations in infancy 总被引:2,自引:0,他引:2
10.
The recognition of transfer-RNA by their cognate aminoacyl-tRNA synthetases is the crucial step in the translation of the genetic code. In order to construct a structural model of the complex between the tyrosyl-tRNA synthetase (TyrTS) from Bacillus stearothermophilus and tRNATyr, 40 basic residues at the surface of the TyrTS dimer have been mutated by site-directed mutagenesis and heterodimers created in vitro by recombining subunits derived from different mutants. As reported here a cluster of basic residues (Arg 207-Lys 208) in the N-terminal domain of one TyrTS subunit interacts with the acceptor stem of tRNATyr and two separated clusters of basic residues (Arg 368-Arg 371; Arg 407-Arg 408-Lys 410-Lys 411) in the C-terminal domain of the other subunit interact with the anticodon arm. The TyrTS would thus clamp the tRNA in a fixed orientation. The precise alignment of the flexible... ACCA 3' end of the tRNA for attack on the tyrosyl adenylate is made by contacts closer to the catalytic groups of the enzyme, such as with Lys 151. 相似文献