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DiMaio F Terwilliger TC Read RJ Wlodawer A Oberdorfer G Wagner U Valkov E Alon A Fass D Axelrod HL Das D Vorobiev SM Iwaï H Pokkuluri PR Baker D 《Nature》2011,473(7348):540-543
Molecular replacement procedures, which search for placements of a starting model within the crystallographic unit cell that best account for the measured diffraction amplitudes, followed by automatic chain tracing methods, have allowed the rapid solution of large numbers of protein crystal structures. Despite extensive work, molecular replacement or the subsequent rebuilding usually fail with more divergent starting models based on remote homologues with less than 30% sequence identity. Here we show that this limitation can be substantially reduced by combining algorithms for protein structure modelling with those developed for crystallographic structure determination. An approach integrating Rosetta structure modelling with Autobuild chain tracing yielded high-resolution structures for 8 of 13 X-ray diffraction data sets that could not be solved in the laboratories of expert crystallographers and that remained unsolved after application of an extensive array of alternative approaches. We estimate that the new method should allow rapid structure determination without experimental phase information for over half the cases where current methods fail, given diffraction data sets of better than 3.2?? resolution, four or fewer copies in the asymmetric unit, and the availability of structures of homologous proteins with >20% sequence identity. 相似文献
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Devkota S Wang Y Musch MW Leone V Fehlner-Peach H Nadimpalli A Antonopoulos DA Jabri B Chang EB 《Nature》2012,487(7405):104-108
The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Here we show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia. This was associated with a pro-inflammatory T helper type 1 (T(H)1) immune response and increased incidence of colitis in genetically susceptible Il10(?/?), but not wild-type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10(?/?) mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts. 相似文献
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The structure of the protein universe and genome evolution 总被引:18,自引:0,他引:18
Despite the practically unlimited number of possible protein sequences, the number of basic shapes in which proteins fold seems not only to be finite, but also to be relatively small, with probably no more than 10,000 folds in existence. Moreover, the distribution of proteins among these folds is highly non-homogeneous -- some folds and superfamilies are extremely abundant, but most are rare. Protein folds and families encoded in diverse genomes show similar size distributions with notable mathematical properties, which also extend to the number of connections between domains in multidomain proteins. All these distributions follow asymptotic power laws, such as have been identified in a wide variety of biological and physical systems, and which are typically associated with scale-free networks. These findings suggest that genome evolution is driven by extremely general mechanisms based on the preferential attachment principle. 相似文献