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71.
Bouvignies G Vallurupalli P Hansen DF Correia BE Lange O Bah A Vernon RM Dahlquist FW Baker D Kay LE 《Nature》2011,477(7362):111-114
Proteins are inherently plastic molecules, whose function often critically depends on excursions between different molecular conformations (conformers). However, a rigorous understanding of the relation between a protein's structure, dynamics and function remains elusive. This is because many of the conformers on its energy landscape are only transiently formed and marginally populated (less than a few per cent of the total number of molecules), so that they cannot be individually characterized by most biophysical tools. Here we study a lysozyme mutant from phage T4 that binds hydrophobic molecules and populates an excited state transiently (about 1?ms) to about 3% at 25?°C (ref. 5). We show that such binding occurs only via the ground state, and present the atomic-level model of the 'invisible', excited state obtained using a combined strategy of relaxation-dispersion NMR (ref. 6) and CS-Rosetta model building that rationalizes this observation. The model was tested using structure-based design calculations identifying point mutants predicted to stabilize the excited state relative to the ground state. In this way a pair of mutations were introduced, inverting the relative populations of the ground and excited states and altering function. Our results suggest a mechanism for the evolution of a protein's function by changing the delicate balance between the states on its energy landscape. More generally, they show that our approach can generate and validate models of excited protein states. 相似文献
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Jex AR Liu S Li B Young ND Hall RS Li Y Yang L Zeng N Xu X Xiong Z Chen F Wu X Zhang G Fang X Kang Y Anderson GA Harris TW Campbell BE Vlaminck J Wang T Cantacessi C Schwarz EM Ranganathan S Geldhof P Nejsum P Sternberg PW Yang H Wang J Wang J Gasser RB 《Nature》2011,479(7374):529-533
Parasitic diseases have a devastating, long-term impact on human health, welfare and food production worldwide. More than two billion people are infected with geohelminths, including the roundworms Ascaris (common roundworm), Necator and Ancylostoma (hookworms), and Trichuris (whipworm), mainly in developing or impoverished nations of Asia, Africa and Latin America. In humans, the diseases caused by these parasites result in about 135,000 deaths annually, with a global burden comparable with that of malaria or tuberculosis in disability-adjusted life years. Ascaris alone infects around 1.2 billion people and, in children, causes nutritional deficiency, impaired physical and cognitive development and, in severe cases, death. Ascaris also causes major production losses in pigs owing to reduced growth, failure to thrive and mortality. The Ascaris-swine model makes it possible to study the parasite, its relationship with the host, and ascariasis at the molecular level. To enable such molecular studies, we report the 273 megabase draft genome of Ascaris suum and compare it with other nematode genomes. This genome has low repeat content (4.4%) and encodes about 18,500 protein-coding genes. Notably, the A. suum secretome (about 750 molecules) is rich in peptidases linked to the penetration and degradation of host tissues, and an assemblage of molecules likely to modulate or evade host immune responses. This genome provides a comprehensive resource to the scientific community and underpins the development of new and urgently needed interventions (drugs, vaccines and diagnostic tests) against ascariasis and other nematodiases. 相似文献
73.
Deciphering the evolution and metabolism of an anammox bacterium from a community genome 总被引:15,自引:0,他引:15
Strous M Pelletier E Mangenot S Rattei T Lehner A Taylor MW Horn M Daims H Bartol-Mavel D Wincker P Barbe V Fonknechten N Vallenet D Segurens B Schenowitz-Truong C Médigue C Collingro A Snel B Dutilh BE Op den Camp HJ van der Drift C Cirpus I van de Pas-Schoonen KT Harhangi HR van Niftrik L Schmid M Keltjens J van de Vossenberg J Kartal B Meier H Frishman D Huynen MA Mewes HW Weissenbach J Jetten MS Wagner M Le Paslier D 《Nature》2006,440(7085):790-794
Anaerobic ammonium oxidation (anammox) has become a main focus in oceanography and wastewater treatment. It is also the nitrogen cycle's major remaining biochemical enigma. Among its features, the occurrence of hydrazine as a free intermediate of catabolism, the biosynthesis of ladderane lipids and the role of cytoplasm differentiation are unique in biology. Here we use environmental genomics--the reconstruction of genomic data directly from the environment--to assemble the genome of the uncultured anammox bacterium Kuenenia stuttgartiensis from a complex bioreactor community. The genome data illuminate the evolutionary history of the Planctomycetes and allow us to expose the genetic blueprint of the organism's special properties. Most significantly, we identified candidate genes responsible for ladderane biosynthesis and biological hydrazine metabolism, and discovered unexpected metabolic versatility. 相似文献
74.
Pounds JA Bustamante MR Coloma LA Consuegra JA Fogden MP Foster PN La Marca E Masters KL Merino-Viteri A Puschendorf R Ron SR Sánchez-Azofeifa GA Still CJ Young BE 《Nature》2006,439(7073):161-167
As the Earth warms, many species are likely to disappear, often because of changing disease dynamics. Here we show that a recent mass extinction associated with pathogen outbreaks is tied to global warming. Seventeen years ago, in the mountains of Costa Rica, the Monteverde harlequin frog (Atelopus sp.) vanished along with the golden toad (Bufo periglenes). An estimated 67% of the 110 or so species of Atelopus, which are endemic to the American tropics, have met the same fate, and a pathogenic chytrid fungus (Batrachochytrium dendrobatidis) is implicated. Analysing the timing of losses in relation to changes in sea surface and air temperatures, we conclude with 'very high confidence' (> 99%, following the Intergovernmental Panel on Climate Change, IPCC) that large-scale warming is a key factor in the disappearances. We propose that temperatures at many highland localities are shifting towards the growth optimum of Batrachochytrium, thus encouraging outbreaks. With climate change promoting infectious disease and eroding biodiversity, the urgency of reducing greenhouse-gas concentrations is now undeniable. 相似文献
75.
Gal-Yam A Fox DB Price PA Ofek EO Davis MR Leonard DC Soderberg AM Schmidt BP Lewis KM Peterson BA Kulkarni SR Berger E Cenko SB Sari R Sharon K Frail D Moon DS Brown PJ Cucchiara A Harrison F Piran T Persson SE McCarthy PJ Penprase BE Chevalier RA MacFadyen AI 《Nature》2006,444(7122):1053-1055
Over the past decade, our physical understanding of gamma-ray bursts (GRBs) has progressed rapidly, thanks to the discovery and observation of their long-lived afterglow emission. Long-duration (> 2 s) GRBs are associated with the explosive deaths of massive stars ('collapsars', ref. 1), which produce accompanying supernovae; the short-duration (< or = 2 s) GRBs have a different origin, which has been argued to be the merger of two compact objects. Here we report optical observations of GRB 060614 (duration approximately 100 s, ref. 10) that rule out the presence of an associated supernova. This would seem to require a new explosive process: either a massive collapsar that powers a GRB without any associated supernova, or a new type of 'engine', as long-lived as the collapsar but without a massive star. We also show that the properties of the host galaxy (redshift z = 0.125) distinguish it from other long-duration GRB hosts and suggest that an entirely new type of GRB progenitor may be required. 相似文献
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Quantum bits (qubits) are the fundamental building blocks of quantum information processors, such as quantum computers. A qubit comprises a pair of well characterized quantum states that can in principle be manipulated quickly compared to the time it takes them to decohere by coupling to their environment. Much remains to be understood about the manipulation and decoherence of semiconductor qubits. Here we show that hydrogen-atom-like motional states of electrons bound to donor impurities in currently available semiconductors can serve as model qubits. We use intense pulses of terahertz radiation to induce coherent, damped Rabi oscillations in the population of two low-lying states of donor impurities in GaAs. Our observations demonstrate that a quantum-confined extrinsic electron in a semiconductor can be coherently manipulated like an atomic electron, even while sharing space with approximately 10(5) atoms in its semiconductor host. We anticipate that this model system will be useful for measuring intrinsic decoherence processes, and for testing both simple and complex manipulations of semiconductor qubits. 相似文献
79.
Kulaga HM Leitch CC Eichers ER Badano JL Lesemann A Hoskins BE Lupski JR Beales PL Reed RR Katsanis N 《Nature genetics》2004,36(9):994-998
Defects in cilia are associated with several human disorders, including Kartagener syndrome, polycystic kidney disease, nephronophthisis and hydrocephalus. We proposed that the pleiotropic phenotype of Bardet-Biedl syndrome (BBS), which encompasses retinal degeneration, truncal obesity, renal and limb malformations and developmental delay, is due to dysfunction of basal bodies and cilia. Here we show that individuals with BBS have partial or complete anosmia. To test whether this phenotype is caused by ciliary defects of olfactory sensory neurons, we examined mice with deletions of Bbs1 or Bbs4. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. Our data indicate that BBS proteins have a role in the microtubule organization of mammalian ciliated cells and that anosmia might be a useful determinant of other pleiotropic disorders with a suspected ciliary involvement. 相似文献
80.
Mammalian centromeres are not defined by a consensus DNA sequence. In all eukaryotes a hallmark of functional centromeres--both normal ones and those formed aberrantly at atypical loci--is the accumulation of centromere protein A (CENP-A), a histone variant that replaces H3 in centromeric nucleosomes. Here we show using deuterium exchange/mass spectrometry coupled with hydrodynamic measures that CENP-A and histone H4 form sub-nucleosomal tetramers that are more compact and conformationally more rigid than the corresponding tetramers of histones H3 and H4. Substitution into histone H3 of the domain of CENP-A responsible for compaction is sufficient to direct it to centromeres. Thus, the centromere-targeting domain of CENP-A confers a unique structural rigidity to the nucleosomes into which it assembles, and is likely to have a role in maintaining centromere identity. 相似文献