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101.
Price JL Shental-Bechor D Dhar A Turner MJ Powers ET Gruebele M Levy Y Kelly JW 《Journal of the American Chemical Society》2010,132(43):15359-15367
Asparagine glycosylation is one of the most common and important post-translational modifications of proteins in eukaryotic cells. N-glycosylation occurs when a triantennary glycan precursor is transferred en bloc to a nascent polypeptide (harboring the N-X-T/S sequon) as the peptide is cotranslationally translocated into the endoplasmic reticulum (ER). In addition to facilitating binding interactions with components of the ER proteostasis network, N-glycans can also have intrinsic effects on protein folding by directly altering the folding energy landscape. Previous work from our laboratories (Hanson et al. Proc. Natl. Acad. Sci. U.S.A. 2009, 109, 3131-3136; Shental-Bechor, D.; Levy, Y. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 8256-8261) suggested that the three sugar residues closest to the protein are sufficient for accelerating protein folding and stabilizing the resulting structure in vitro; even a monosaccharide can have a dramatic effect. The highly conserved nature of these three proximal sugars in N-glycans led us to speculate that introducing an N-glycosylation site into a protein that is not normally glycosylated would stabilize the protein and increase its folding rate in a manner that does not depend on the presence of specific stabilizing protein-saccharide interactions. Here, we test this hypothesis experimentally and computationally by incorporating an N-linked GlcNAc residue at various positions within the Pin WW domain, a small β-sheet-rich protein. The results show that an increased folding rate and enhanced thermodynamic stability are not general, context-independent consequences of N-glycosylation. Comparison between computational predictions and experimental observations suggests that generic glycan-based excluded volume effects are responsible for the destabilizing effect of glycosylation at highly structured positions. However, this reasoning does not adequately explain the observed destabilizing effect of glycosylation within flexible loops. Our data are consistent with the hypothesis that specific, evolved protein-glycan contacts must also play an important role in mediating the beneficial energetic effects on protein folding that glycosylation can confer. 相似文献
102.
An efficient four-step synthesis of PA-824, a promising antituberculosis drug candidate, has been developed. This concise approach offers significant improvements over the synthetic route currently used for large-scale production. 相似文献
103.
Heterodyne near-field scanning optical microscopy (H-NSOM) has proven useful as a tool for characterization of both amplitude and phase of on-chip photonic devices in air, but it has previously been unable to characterize devices with a dielectric overcladding, which is commonly used in practice for such devices. Here we demonstrate H-NSOM of a silicon waveguide with a liquid cladding emulating the solid dielectric. This technique allows characterization of practical devices with realistic refractive index profiles. Fourier analysis is used to estimate the effective refractive index of the mode from the measured data, showing an index shift of 0.08 from air to water cladding, which is seen to correspond well to simulations. 相似文献
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We prove a weak version of Hardy’s uncertainty principle using properties of the prolate spheroidal wave functions. We describe the eigenvalues of the sum of a time limiting operator and a band limiting operator acting on \(L^2(\mathbb {R})\) . A weak version of Hardy’s uncertainty principle follows from the asymptotic behavior of the largest eigenvalue as the time limit and the band limit approach infinity. An asymptotic formula for this eigenvalue is obtained from its well-known counterpart for the prolate integral operator. 相似文献
107.
Gerd Finke Pierre Lemaire Jean-Marie Proth Maurice Queyranne 《European Journal of Operational Research》2009,199(3):702-705
In this paper, we present a new objective function for scheduling on parallel machines: minimizing the number of machines for schedules of minimum length. We study its complexity and we prove the NP-completeness of this problem, even if there is no precedences or for unitary execution times. We propose several polynomial algorithms for various particular cases. 相似文献
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New 4-aminoquinolines having a -CF2CH-(heteroaryl)-OH moiety are obtained in moderate yields from the electrochemical catalyzed reaction of the corresponding 4-amino-3-chlorodifluoroacetyl-2-methoxyquinoline in the presence of heteroaryl aldehydes. A one-pot intramolecular zinc mediated aromatic nucleophilic substitution also gave access to novel difluorinated 5-aminodihydropyrano[2,3-b]quinolin-4-ones. 相似文献