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21.
In a continuing effort to explore structural and functional dynamics in RNA catalysis, we have created a series of allosteric hammerhead ribozymes that are activated by theophylline. Representative ribozymes exhibit greater than 3000-fold activation upon effector-binding and cleave with maximum rate constants that are equivalent to the unmodified hammerhead ribozyme. In addition, we have evolved a variant allosteric ribozyme that exhibits an effector specificity change from theophylline to 3-methylxanthine. Molecular discrimination between the two effectors appears to be mediated by subtle conformational differences that originate from displacement of the phosphodiester backbone near the effector binding pocket. These findings reveal the importance of abstruse aspects of molecular recognition by nucleic acids that are likely to be unapproachable by current methods of rational design. 相似文献
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Kate?ina Ku?elová Barbora Brodská Ota Fuchs Marie Dobrovolná Petr Soukup Petr Cetkovsky 《PloS one》2015,10(5)
Nucleophosmin 1 (NPM1) mutations are frequently found in patients with acute myeloid leukemia (AML) and the newly generated sequences were suggested to induce immune response contributing to the relatively favorable outcome of patients in this AML subset. We hypothesized that if an efficient immune response against mutated nucleophosmin can be induced in vivo, the individuals expressing HLA alleles suitable for presenting NPM-derived peptides should be less prone to developing AML associated with NPM1 mutation. We thus compared HLA class I frequencies in a cohort of patients with mutated NPM1 (63 patients, NPMc+), a cohort of patients with wild-type NPM1 (94 patients, NPMwt) and in normal individuals (large datasets available from Allele Frequency Net Database). Several HLA allelic groups were found to be depleted in NPMc+ patients, but not in NPMwt compared to the normal distribution. The decrease was statistically significant for HLA B*07, B*18, and B*40. Furthermore, statistically significant advantage in the overall survival was found for patients with mutated NPM1 expressing at least one of the depleted allelic groups. The majority of the depleted alleles were predicted to bind potent NPM-derived immunopeptides and, importantly, these peptides were often located in the unmutated part of the protein. Our analysis suggests that individuals expressing specific HLA allelic groups are disposed to develop an efficient anti-AML immune response thanks to aberrant cytoplasmic localization of the mutated NPM protein. 相似文献
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Pascal Maurice Avais M Daulat Rostislav Turecek Klara Ivankova-Susankova Francesco Zamponi Maud Kamal Nathalie Clement Jean-Luc Guillaume Bernhard Bettler C��line Gal��s Philippe Delagrange Ralf Jockers 《The EMBO journal》2010,29(21):3646-3659
Functional asymmetry of G‐protein‐coupled receptor (GPCR) dimers has been reported for an increasing number of cases, but the molecular architecture of signalling units associated to these dimers remains unclear. Here, we characterized the molecular complex of the melatonin MT1 receptor, which directly and constitutively couples to Gi proteins and the regulator of G‐protein signalling (RGS) 20. The molecular organization of the ternary MT1/Gi/RGS20 complex was monitored in its basal and activated state by bioluminescence resonance energy transfer between probes inserted at multiple sites of the complex. On the basis of the reported crystal structures of Gi and the RGS domain, we propose a model wherein one Gi and one RGS20 protein bind to separate protomers of MT1 dimers in a pre‐associated complex that rearranges upon agonist activation. This model was further validated with MT1/MT2 heterodimers. Collectively, our data extend the concept of asymmetry within GPCR dimers, reinforce the notion of receptor specificity for RGS proteins and highlight the advantage of GPCRs organized as dimers in which each protomer fulfils its specific task by binding to different GPCR‐interacting proteins. 相似文献
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Doris Freißmuth Alexander Hiltgartner Christiane Stahl‐Hennig Dietmar Fuchs Klara Tenner‐Racz Paul Racz Klaus Überla Alexander Strasak Manfred P. Dierich Heribert Stoiber Barbara Falkensammer 《Journal of medical primatology》2010,39(2):97-111
Background To determine the correlation between protection and humoral immune response against simian immunodeficiency virus (SIVmac251), 11 macaques were immunized with live‐attenuated SIVmac239Δnef either intravenously or via the tonsils and exposed to SIVmac251 after either 6 or 15 months along with unvaccinated controls. Results Independent of the route of vaccine application, viremia was significantly reduced in vaccinees compared with controls 2 weeks post‐challenge. Concomitantly, viremia correlated inversely with SIV‐specific IgG, complement‐mediated lysis and neutralizing antibodies and these parameters seemed to contribute to reduced viremia. During chronic infection, six monkeys controlled viremia in the circulation (two or fewer infectious units per 106 PBMCs) and showed no signs of trapping in lymphatic tissues (Appendix S1). Conclusions As no significant differences were observed throughout the study, with respect to the humoral immune response and viremia control, between the two vaccinated cohorts, mucosal immunization strategies are recommended due to more simplified application. 相似文献
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Few studies have examined exodermal development in relation to the formation of barriers to both radial oxygen loss (ROL) and solute penetration along growing roots. Here, we report on the structural development, chemical composition and functional properties of the exodermis in two diverse wetland grasses, Glyceria maxima and Phragmites australis. Anatomical features, development, the biochemical composition of exodermal suberin and the penetration of apoplastic tracers and oxygen were examined. Striking interspecific differences in exodermal structure, suberin composition and quantity per unit surface area, and developmental changes along the roots were recorded. Towards the root base, ROL and periodic acid (H(5)IO(6)) penetration were virtually stopped in P. australis; in G. maxima, a tight ROL barrier restricted but did not stop H(5)IO(6) penetration and the exodermis failed to stain with lipidic dyes. Cultivation in stagnant deep hypoxia conditions or oxygenated circulating solution affected the longitudinal pattern of ROL profiles in G. maxima but statistically significant changes in exodermal suberin composition or content were not detected. Interspecific differences in barrier performance were found to be related to hypodermal structure and probably to qualitative as well as quantitative variations in suberin composition and distribution within exodermal cell walls. Implications for root system function are discussed, and it is emphasized that sufficient spatial resolution to identify the effects of developmental changes along roots is crucial for realistic evaluation of exodermal barrier properties. 相似文献
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Dual effect of acid pH on purinergic P2X3 receptors depends on the histidine 206 residue 总被引:1,自引:0,他引:1
Gerevich Z Zadori ZS Köles L Kopp L Milius D Wirkner K Gyires K Illes P 《The Journal of biological chemistry》2007,282(47):33949-33957
Whole cell patch clamp investigations were carried out to clarify the pH sensitivity of native and recombinant P2X(3) receptors. In HEK293 cells permanently transfected with human (h) P2X(3) receptors (HEK293-hP2X(3) cells), an acidic pH shifted the concentration-response curve for alpha,beta-methylene ATP (alpha,beta-meATP) to the right and increased its maximum. An alkalic pH did not alter the effect of alpha,beta-meATP. Further, a low pH value increased the activation time constant (tau(on)) of the alpha,beta-meATP current; the fast and slow time constants of desensitization (tau(des1), tau(des2)) were at the same time also increased. Finally, acidification accelerated the recovery of P2X(3) receptors from the desensitized state. Replacement of histidine 206, but not histidine 45, by alanine abolished the pH-induced effects on hP2X(3) receptors transiently expressed in HEK293 cells. Changes in the intracellular pH had no effect on the amplitude or time course of the alpha,beta-meATP currents. The voltage sensitivity and reversal potential of the currents activated by alpha,beta-meATP were unaffected by extracellular acidification. Similar effects were observed in a subpopulation of rat dorsal root ganglion neurons expressing homomeric P2X(3) receptor channels. It is suggested that acidification may have a dual effect on P2X(3) channels, by decreasing the current amplitude at low agonist concentrations (because of a decrease in the rate of activation) and increasing it at high concentrations (because of a decrease in the rate of desensitization). Thereby, a differential regulation of pain sensation during e.g. inflammation may occur at the C fiber terminals of small DRG neurons in peripheral tissues. 相似文献