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A series of novel (3′-amino-[1,1′-biphenyl]-4-yl) sulfamic acid derivatives were designed as nonphosphonate-based phosphotyrosy (pTyr) mimetics, synthesized and screened for use as HPTPβ inhibitors. Compounds C22 and C2 showed favorable HPTPβ inhibitory activity and better selectivity for HPTPβ than for PTP1B and SHP2. Docking results suggested that compounds C2 and C22 could not only efficiently fit into the catalytic site of the HPTPβ enzyme but also interact with the Lys1807, Arg1809 and Lys1811 residues of the secondary binding site, which was next to the catalytic center of the enzyme. The mode of interaction of the synthesized compound with the protein was different from the one found in a complex crystal of small molecules with HPTPβ (2I4H), in which the inhibitory molecule formed hydrogen bonds with the Gln1948 and Asn1735 residues of the secondary binding site. 相似文献
804.
《Bioorganic & medicinal chemistry》2016,24(20):4768-4778
805.
Rational design of a monomeric and photostable far‐red fluorescent protein for fluorescence imaging in vivo
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William Clay Gustafson Rubén Ruiz‐González Luca Signor Fanny Marzocca Franck Borel Matthew P. Klassen Kalpana Makhijani Antoine Royant Yuh‐Nung Jan William A. Weiss Su Guo Xiaokun Shu 《Protein science : a publication of the Protein Society》2016,25(2):308-315
Fluorescent proteins (FPs) are powerful tools for cell and molecular biology. Here based on structural analysis, a blue‐shifted mutant of a recently engineered monomeric infrared fluorescent protein (mIFP) has been rationally designed. This variant, named iBlueberry, bears a single mutation that shifts both excitation and emission spectra by approximately 40 nm. Furthermore, iBlueberry is four times more photostable than mIFP, rendering it more advantageous for imaging protein dynamics. By tagging iBlueberry to centrin, it has been demonstrated that the fusion protein labels the centrosome in the developing zebrafish embryo. Together with GFP‐labeled nucleus and tdTomato‐labeled plasma membrane, time‐lapse imaging to visualize the dynamics of centrosomes in radial glia neural progenitors in the intact zebrafish brain has been demonstrated. It is further shown that iBlueberry can be used together with mIFP in two‐color protein labeling in living cells and in two‐color tumor labeling in mice. 相似文献
806.
Doo Nam Kim Timothy M. Jacobs Brian Kuhlman 《Protein science : a publication of the Protein Society》2016,25(3):702-710
β‐sheets often have one face packed against the core of the protein and the other facing solvent. Mutational studies have indicated that the solvent‐facing residues can contribute significantly to protein stability, and that the preferred amino acid at each sequence position is dependent on the precise structure of the protein backbone and the identity of the neighboring amino acids. This suggests that the most advantageous methods for designing β‐sheet surfaces will be approaches that take into account the multiple energetic factors at play including side chain rotamer preferences, van der Waals forces, electrostatics, and desolvation effects. Here, we show that the protein design software Rosetta, which models these energetic factors, can be used to dramatically increase protein stability by optimizing interactions on the surfaces of small β‐sheet proteins. Two design variants of the β‐sandwich protein from tenascin were made with 7 and 14 mutations respectively on its β‐sheet surfaces. These changes raised the thermal midpoint for unfolding from 45°C to 64°C and 74°C. Additionally, we tested an empirical approach based on increasing the number of potential salt bridges on the surfaces of the β‐sheets. This was not a robust strategy for increasing stability, as three of the four variants tested were unfolded. 相似文献
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Xiaoling Zhang Qi Shen Bo Tang Huanhuan Liang Luhua Lai 《Protein science : a publication of the Protein Society》2016,25(11):2066-2075
De novo protein design offers templates for engineering tailor‐made protein functions and orthogonal protein interaction networks for synthetic biology research. Various computational methods have been developed to introduce functional sites in known protein structures. De novo designed protein scaffolds provide further opportunities for functional protein design. Here we demonstrate the rational design of novel tumor necrosis factor alpha (TNFα) binding proteins using a home‐made grafting program AutoMatch. We grafted three key residues from a virus 2L protein to a de novo designed small protein, DS119, with consideration of backbone flexibility. The designed proteins bind to TNFα with micromolar affinities. We further optimized the interface residues with RosettaDesign and significantly improved the binding capacity of one protein Tbab1‐4. These designed proteins inhibit the activity of TNFα in cellular luciferase assays. Our work illustrates the potential application of the de novo designed protein DS119 in protein engineering, biomedical research, and protein sequence‐structure‐function studies. 相似文献
809.
Cristina Moya Kristin Snopkowski Rebecca Sear 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2016,371(1692)
Several empirical observations suggest that when women have more autonomy over their reproductive decisions, fertility is lower. Some evolutionary theorists have interpreted this as evidence for sexual conflicts of interest, arguing that higher fertility is more adaptive for men than women. We suggest the assumptions underlying these arguments are problematic: assuming that women suffer higher costs of reproduction than men neglects the (different) costs of reproduction for men; the assumption that men can repartner is often false. We use simple models to illustrate that (i) men or women can prefer longer interbirth intervals (IBIs), (ii) if men can only partner with wives sequentially they may favour shorter IBIs than women, but such a strategy would only be optimal for a few men who can repartner. This suggests that an evolved universal male preference for higher fertility than women prefer is implausible and is unlikely to fully account for the empirical data. This further implies that if women have more reproductive autonomy, populations should grow, not decline. More precise theoretical explanations with clearly stated assumptions, and data that better address both ultimate fitness consequences and proximate psychological motivations, are needed to understand under which conditions sexual conflict over reproductive timing should arise. 相似文献
810.
Tuğba Keskin Gündoğdu İrem Deniz Gülizar Çalışkan Erdem Sefa Şahin 《Critical reviews in biotechnology》2016,36(2):368-388
Experimental design is a form of process analysis in which certain factors are selected to obtain the desired responses of interest. It may also be used for the determination of the effects of various independent factors on a dependent factor. The bioengineering discipline includes many different areas of scientific interest, and each study area is affected and governed by many different factors. Briefly analyzing the important factors and selecting an experimental design for optimization are very effective tools for the design of any bioprocess under question. This review summarizes experimental design methods that can be used to investigate various factors relating to bioengineering processes. The experimental methods generally used in bioengineering are as follows: full factorial design, fractional factorial design, Plackett–Burman design, Taguchi design, Box–Behnken design and central composite design. These design methods are briefly introduced, and then the application of these design methods to study different bioengineering processes is analyzed. 相似文献