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991.
Lambert LJ Bobkov AA Smith JW Marassi FM 《The Journal of biological chemistry》2008,283(24):16665-16672
Integrin alpha2beta1 is a major receptor required for activation and adhesion of platelets, through the specific recognition of collagen by the alpha2-I domain (alpha2-I), which binds fibrillar collagen via Mg(2+)-bridged interactions. The crystal structure of a truncated form of the alpha2-I domain, bound to a triple helical collagen peptide, revealed conformational changes suggestive of a mechanism where the ligand-bound I domain can initiate and propagate conformational change to the full integrin complex. Collagen binding by alpha2-I and fibrinogen-dependent platelet activity can be inhibited by snake venom polypeptides. Here we describe the inhibitory effect of a short cyclic peptide derived from the snake toxin metalloprotease jararhagin, with specific amino acid sequence RKKH, on the ability of alpha2-I to bind triple helical collagen. Isothermal titration calorimetry measurements showed that the interactions of alpha2-I with collagen or RKKH peptide have similar affinities, and NMR chemical shift mapping experiments with (15)N-labeled alpha2-I, and unlabeled RKKH peptide, indicate that the peptide competes for the collagen-binding site of alpha2-I but does not induce a large scale conformational rearrangement of the I domain. 相似文献
992.
Flock U Thorndycroft FH Matorin AD Richardson DJ Watmough NJ Adelroth P 《The Journal of biological chemistry》2008,283(7):3839-3845
The bacterial respiratory nitric-oxide reductase (NOR) is a member of the superfamily of O(2)-reducing, proton-pumping, heme-copper oxidases. Even although nitric oxide reduction is a highly exergonic reaction, NOR is not a proton pump and rather than taking up protons from the cytoplasmic (membrane potential-negative) side of the membrane, like the heme-copper oxidases, NOR derives its substrate protons from the periplasmic (membrane potential-positive) side of the membrane. The molecular details of this non-electrogenic proton transfer are not yet resolved, so in this study we have explored a role in a proposed proton pathway for a conserved surface glutamate (Glu-122) in the catalytic subunit (NorB). The effect of substituting Glu-122 with Ala, Gln, or Asp on a single turnover of the reduced NOR variants with O(2), an alternative and experimentally tractable substrate for NOR, was determined. Electron transfer coupled to proton uptake to the bound O(2) is severely and specifically inhibited in both the E122A and E122Q variants, establishing the importance of a protonatable side chain at this position. In the E122D mutant, proton uptake is retained but it is associated with a significant increase in the observed pK(a) of the group donating protons to the active site. This suggests that Glu-122 is important in defining this proton donor. A second nearby glutamate (Glu-125) is also required for the electron transfer coupled to proton uptake, further emphasizing the importance of this region of NorB in proton transfer. Because Glu-122 is predicted to lie near the periplasmic surface of NOR, the results provide strong experimental evidence that this residue contributes to defining the aperture of a non-electrogenic "E-pathway" that serves to deliver protons from the periplasm to the buried active site in NOR. 相似文献
993.
Babenko AP 《The Journal of biological chemistry》2008,283(14):8778-8782
ATP/ADP-sensing (sulfonylurea receptor (SUR)/K(IR)6)(4) K(ATP) channels regulate the excitability of our insulin secreting and other vital cells via the differential MgATP/ADP-dependent stimulatory actions of their tissue-specific ATP-binding cassette regulatory subunits (sulfonylurea receptors), which counterbalance the nearly constant inhibitory action of ATP on the K(+) inwardly rectifying pore. Mutations in SUR1 that abolish its stimulation have been found in infants persistently releasing insulin. Activating mutations in SUR1 have been shown to cause neonatal diabetes. Here, analyses of K(IR)6.2-based channels with diabetogenic receptors reveal that MgATP-dependent hyper-stimulation of mutant SUR can compromise the ability of K(ATP) channels to function as metabolic sensors. I demonstrate that the channel hyperactivity rises exponentially with the number of hyperstimulating subunits, so small subpopulations of channels with more than two mutant SUR can dominate hyperpolarizing currents in heterozygous patients. I uncovered an attenuated tolbutamide inhibition of the hyperstimulated mutant, which is normally sensitive to the drug under non-stimulatory conditions. These findings show the key role of SUR in sensing the metabolic index in humans and urge others to (re)test mutant SUR/K(IR)6 channels from probands in physiologic MgATP. 相似文献
994.
Liu F Kovalevsky AY Tie Y Ghosh AK Harrison RW Weber IT 《Journal of molecular biology》2008,381(1):102-115
HIV-1 (human immunodeficiency virus type 1) protease (PR) and its mutants are important antiviral drug targets. The PR flap region is critical for binding substrates or inhibitors and catalytic activity. Hence, mutations of flap residues frequently contribute to reduced susceptibility to PR inhibitors in drug-resistant HIV. Structural and kinetic analyses were used to investigate the role of flap residues Gly48, Ile50, and Ile54 in the development of drug resistance. The crystal structures of flap mutants PRI50V (PR with I50V mutation), PRI54V (PR with I54V mutation), and PRI54M (PR with I54M mutation) complexed with saquinavir (SQV) as well as PRG48V (PR with G48V mutation), PRI54V, and PRI54M complexed with darunavir (DRV) were determined at resolutions of 1.05-1.40 Å. The PR mutants showed changes in flap conformation, interactions with adjacent residues, inhibitor binding, and the conformation of the 80s loop relative to the wild-type PR. The PR contacts with DRV were closer in PRG48V-DRV than in the wild-type PR-DRV, whereas they were longer in PRI54M-DRV. The relative inhibition of PRI54V and that of PRI54M were similar for SQV and DRV. PRG48V was about twofold less susceptible to SQV than to DRV, whereas the opposite was observed for PRI50V. The observed inhibition was in agreement with the association of G48V and I50V with clinical resistance to SQV and DRV, respectively. This analysis of structural and kinetic effects of the mutants will assist in the development of more effective inhibitors for drug-resistant HIV. 相似文献
995.
996.
Irina G Moiseyeva Michael N Romanov Andrey A Nikiforov Antonina A Sevastyanova Serafima K Semyenova 《遗传、选种与进化》2003,35(5):403-423
Published results were reassessed and original data are provided regarding the origin and relatedness of four postulated chicken breed lineages, egg-type, game, meat-type and Bantam, to each other and to the basic ancestral species of jungle fowls, Gallus gallus. A system approach was employed concerning the planning of the experiments. One element of the system approach is the choice of the breeds to be compared with G. gallus. These breeds were supposed to represent major evolutionary branches of chickens. Four experiments on genetic relationships were conducted using different estimation criteria including morphological discrete characters, body measurements, biochemical markers, and the activity of serum esterase-1. The greatest similarity was found between G. gallus and the egg-type breeds of Mediterranean roots and/or true Bantams. This fact might testify that the indicated chicken groups occupied earlier stages in the evolution from the wild progenitor to the present biodiversity of chickens in the world. 相似文献
997.
Kurets V. K. Drozdov S. N. Popov E. G. Dembo E. D. Khilkov N. I. Trofimova S. A. 《Russian Journal of Plant Physiology》2003,50(3):308-313
Effects and aftereffects of typical temperatures of cultivar habitat (background temperature), heat-hardening, and cold-hardening temperatures on dark respiration of leaf segments and intact plants were investigated on plant species differing in cold tolerance—cucumber (Cucumis sativus L.), tomato (Lycopersicon esculentum Mill.), cicer milkvetch (Astragalus cicer L.), and narrow-leaved lupine (Lupinus angustifolium L.). At cold-hardening temperatures, the respiratory metabolism underwent rearrangements serving to compensate for elevated energy losses during plant adaptation. This was manifested in the increase in the respiratory coefficient (RC) and the Q
10 coefficient during hardening. The preconditioning of plants at hardening temperatures enhanced O2 uptake and elevated the ratio of growth respiration to maintenance respiration in the post-treatment period. Conversely, temperature variations within the background range had no aftereffect on RC, Q
10, and O2 uptake. 相似文献
998.
Hanna Julienne Vincent Laville Zachary R. McCaw Zihuai He Vincent Guillemot Carla Lasry Andrey Ziyatdinov Cyril Nerin Amaury Vaysse Pierre Lechat Herv Mnager Wilfried Le Goff Marie-Pierre Dube Peter Kraft Iuliana Ionita-Laza Bjarni J. Vilhjlmsson Hugues Aschard 《PLoS genetics》2021,17(8)
Genome-wide association studies (GWASs) have uncovered a wealth of associations between common variants and human phenotypes. Here, we present an integrative analysis of GWAS summary statistics from 36 phenotypes to decipher multitrait genetic architecture and its link with biological mechanisms. Our framework incorporates multitrait association mapping along with an investigation of the breakdown of genetic associations into clusters of variants harboring similar multitrait association profiles. Focusing on two subsets of immunity and metabolism phenotypes, we then demonstrate how genetic variants within clusters can be mapped to biological pathways and disease mechanisms. Finally, for the metabolism set, we investigate the link between gene cluster assignment and the success of drug targets in randomized controlled trials. 相似文献
999.
O,O′-Dipropyldithiophosphate and O,O′-dibutyldithiophosphate (Dtph) cadmium(II) complexes were prepared and studied by means of heteronuclear 31P, 113Cd, 31C CP/MAS NMR spectroscopy and single-crystal X-ray diffraction. Linear-chain polynuclear structures have been established for both cadmium(II) complexes, in which each pair of equivalent dithiophosphate groups, playing the same bridging structural function, asymmetrically links the neighbouring cadmium atoms. One remarkable structural feature of the synthesised cadmium(II) compounds is defined by the alternation of two types of conformationally different (‘chair’-‘saddle’) eight-membered rings [Cd2S4P2] in the polymeric chains. Therefore, in both 31P NMR and XRD data, the bridging dithiophosphate ligands exhibit structural inequivalence in pairs. The structural states of both Dtph ligands and cadmium atoms have been characterised by the 31P and 113Cd chemical shift tensors, which display a profound axially symmetric and mainly rhombic characters, respectively. All experimental 31P resonances were assigned to the phosphorus structural sites in both resolved structures. 相似文献
1000.
Hiraku Takada Caillan Crowe-McAuliffe Christine Polte Zhanna Yu Sidorova Victoriia Murina Gemma C Atkinson Andrey L Konevega Zoya Ignatova Daniel
N Wilson Vasili Hauryliuk 《Nucleic acids research》2021,49(14):8355
In the cell, stalled ribosomes are rescued through ribosome-associated protein quality-control (RQC) pathways. After splitting of the stalled ribosome, a C-terminal polyalanine ‘tail’ is added to the unfinished polypeptide attached to the tRNA on the 50S ribosomal subunit. In Bacillus subtilis, polyalanine tailing is catalyzed by the NEMF family protein RqcH, in cooperation with RqcP. However, the mechanistic details of this process remain unclear. Here we demonstrate that RqcH is responsible for tRNAAla selection during RQC elongation, whereas RqcP lacks any tRNA specificity. The ribosomal protein uL11 is crucial for RqcH, but not RqcP, recruitment to the 50S subunit, and B. subtilis lacking uL11 are RQC-deficient. Through mutational mapping, we identify critical residues within RqcH and RqcP that are important for interaction with the P-site tRNA and/or the 50S subunit. Additionally, we have reconstituted polyalanine-tailing in vitro and can demonstrate that RqcH and RqcP are necessary and sufficient for processivity in a minimal system. Moreover, the in vitro reconstituted system recapitulates our in vivo findings by reproducing the importance of conserved residues of RqcH and RqcP for functionality. Collectively, our findings provide mechanistic insight into the role of RqcH and RqcP in the bacterial RQC pathway. 相似文献