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Philippe Noriel Q. Pascua Min-Suk Song Jun Han Lee Kuk Jin Park Hyeok-il Kwon Yun Hee Baek Seung-Pyo Hong Jong-Bok Rho Chul-Joong Kim Haryoung Poo Thomas S. Ryoo Moon-Hee Sung Young Ki Choi 《PloS one》2009,4(12)
The current pandemic (H1N1) 2009 virus remains transmissible among humans worldwide with cases of reverse zoonosis, providing opportunities to produce more pathogenic variants which could pose greater human health concerns. To investigate whether recent seasonal human or swine H1N1 vaccines could induce cross-reactive immune responses against infection with the pandemic (H1N1) 2009 virus, mice, ferrets or mini-pigs were administered with various regimens (once or twice) and antigen content (1.77, 3.5 or 7.5 µg HA) of a-Brsibane/59/07, a-CAN01/04 or RgCA/04/09xPR8 vaccine. Receipt of a-CAN01/04 (2-doses) but not a-Brisbane/59/07 induced detectable but modest (20–40 units) cross-reactive serum antibody against CA/04/09 by hemagglutinin inhibition (HI) assays in mice. Only double administration (7.5 µg HA) of both vaccine in ferrets could elicit cross-reactivity (30–60 HI titers). Similar antigen content of a-CAN01/04 in mini-pigs also caused a modest ∼30 HI titers (twice vaccinated). However, vaccine-induced antibody titers could not suppress active virus replication in the lungs (mice) or virus shedding (ferrets and pigs) of immunized hosts intranasally challenged with CA/04/09. Furthermore, neither ferrets nor swine could abrogate aerosol transmission of the virus into naïve contact animals. Altogether, these results suggest that neither recent human nor animal H1N1 vaccine could provide complete protectivity in all animal models. Thus, this study warrants the need for strain-specific vaccines that could yield the optimal protection desired for humans and/or animals. 相似文献
235.
Je-Hyun Baek Won Suk Yang Cheolju Lee Myeong-Hee Yu 《Molecular & cellular proteomics : MCP》2009,8(5):1072-1081
The native state of α1-antitrypsin (α1AT), a member of the serine protease inhibitor (serpin) family, is considered a kinetically trapped folding intermediate that converts to a more stable form upon complex formation with a target protease. Although previous structural and mutational studies of α1AT revealed the structural basis of the native strain and the kinetic trap, the mechanism of how the native molecule overcomes the kinetic barrier to reach the final stable conformation during complex formation remains unknown. We hypothesized that during complex formation, a substantial portion of the molecule undergoes unfolding, which we dubbed functional unfolding. Hydrogen-deuterium exchange coupled with ESI-MS was used to analyze this serpin in three forms: native, complexing, and complexed with bovine β-trypsin. Comparing the deuterium content at the corresponding regions of these three samples, we probed the unfolding of α1AT during complex formation. A substantial portion of the α1AT molecule unfolded transiently during complex formation, including not only the regions expected from previous structural studies, such as the reactive site loop, helix F, and the following loop, but also regions not predicted previously, such as helix A, strand 6 of β-sheet B, and the N terminus. Such unfolding of the native interactions may elevate the free energy level of the kinetically trapped native serpin sufficiently to cross the transition state during complex formation. In the current study, we provide evidence that protein unfolding has to accompany functional execution of the protein molecule.The native strain of serine protease inhibitors (serpins)1 is considered to be crucial to their biological functions, such as plasma protease inhibition (1, 2) and hormone delivery (3). Functional execution of serpins is accompanied by the conversion of the strained native structure into a more stable conformation (4). Because some of the strained native serpin structures are spontaneously converted into a more relaxed stable latent form under physiological conditions (5–7), the native structure is not the thermodynamically most stable conformation but is a kinetically trapped conformation. Upon binding a target protease, the scissile bond of the reactive site loop (RSL) is cleaved while the protease is covalently attached to the N-terminal part of the RSL (8, 9). During the conversion of the strained structure into the stable complex conformation (Fig. 1), RSL is inserted into the central β-sheet (A sheet) between strands 3 and 5 (s3A and s5A) to form strand 4 (s4A), and the covalently attached protease is concomitantly translocated to the opposite pole (10). Serpin inhibition occurs via a suicide substrate mechanism (4, 11, 12) in which serpins, upon binding proteases, partition between cleaved serpins and stable serpin-enzyme complexes.Open in a separate windowFig. 1.Structures of native α1AT and α1AT-trypsin complex. Left, structure of native α1AT (Protein Data Bank code 1QLP) illustrated with secondary structural elements (1). Right, structure of α1AT-trypsin complex (Protein Data Bank code 1EZX). The nine α-helices are colored dark gray, and the 16 β-strands are colored light gray.As a member of the serpin family, α1-antitrypsin (α1AT), which serves to modulate the activity of human leukocyte elastase in the lung, has been most extensively studied with regard to both structure and inhibition mechanism. Our previous studies with stabilizing mutations of α1AT showed that the native strain is distributed throughout the molecule and that various unfavorable structural motifs, such as hydrophobic packing, cavity in the core, and surface hydrophobic patch, appear to maintain the native strain (13, 14). Indeed stabilizing mutations localized in the region of RSL insertion during complex formation affected the inhibitory function individually by retarding the loop insertion (15). Mutations in other regions did not affect the inhibitory function individually, but collectively these mutations affected the inhibitory function when the stabilization effect reached a certain threshold (16). Maintaining the kinetic trap appears to require sustaining RSL at the hydrophobic β-barrel composed of sheet B and sheet C (B/C β-barrel) because the conversion into the stable latent conformation occurs by destabilization of the B/C β-barrel (6) as well as by the extension of RSL length (17). Thus, upon binding a target protease, RSL cleavage appears to induce a conformational conversion, and the resultant strain throughout the molecule facilitates the opening of β-sheet A and the insertion of the RSL, which is critical for the inhibitory pathway as opposed to the substrate pathway (10).Although these structural and mutational studies revealed the structural basis for maintaining the kinetic trap and its relation to the inhibitory mechanism, several questions still remain. For example, what structural changes does the native serpin molecule undergo to overcome the kinetic barrier and reach the final stable conformation during the complex formation? In the present study, to probe the structural process of overcoming the kinetic barrier during complex formation with a target protease, amide hydrogen exchange (hydrogen-deuterium exchange (H/D-EX)) was explored during the conversion of the native α1AT to the stable complex. H/D-EX coupled with ESI-MS is a powerful analytical tool for observing protein dynamics, transient conformational changes, and protein-protein interactions (18–22). These experiments demonstrated that transient structural unfolding occurred in many regions in the α1AT molecule during formation of the complex with β-trypsin, and some of this unfolding was unpredicted from previous structural studies. 相似文献
236.
Cho SY Baek JY Han SS Kang SK Ha JD Ahn JH Lee JD Kim KR Cheon HG Rhee SD Yang SD Yon GH Pak CS Choi JK 《Bioorganic & medicinal chemistry letters》2006,16(3):499-502
A series of novel cyclopenta[d][1,2]-oxazine derivatives was prepared and evaluated for their inhibitory activity toward protein tyrosine phosphatase 1B (PTP-1B). Compound 6s was found to be an inhibitor of PTP-1B with nanomolar IC(50) value and high level of selectivity over other recombinant phosphatases. 相似文献
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Anna G. U. S. Newcomb Seungwon Baek Brian P. Kelly 《Computer methods in biomechanics and biomedical engineering》2017,20(2):182-192
Angled screw insertion has been advocated to enhance fixation strength during posterior spine fixation. Stresses on a pedicle screw and surrounding vertebral bone with different screw angles were studied by finite element analysis during simulated multidirectional loading. Correlations between screw-specific vertebral geometric parameters and stresses were studied. Angulations in both the sagittal and axial planes affected stresses on the cortical and cancellous bones and the screw. Pedicle screws pointing laterally (vs. straight or medially) in the axial plane during superior screw angulation may be advantageous in terms of reducing the risk of both screw loosening and screw breakage. 相似文献
239.
Contribution of autophagy and regulation of related proteins to the degeneration of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD) remain unknown. We report that upregulation of KRT8 (keratin 8) as well as its phosphorylation are accompanied with autophagy and attenuated with the inhibition of autophagy in RPE cells under oxidative stress. KRT8 appears to have a dual role in RPE pathophysiology. While increased expression of KRT8 following autophagy provides a cytoprotective role in RPE, phosphorylation of KRT8 induces pathologic epithelial-mesenchymal transition (EMT) of RPE cells under oxidative stress, which is mediated by MAPK1/ERK2 (mitogen-activated protein kinase 1) and MAPK3/ERK1. Inhibition of autophagy further promotes EMT, which can be reversed by inhibition of MAPK. Thus, regulated enhancement of autophagy with concurrent increased expression of KRT8 and the inhibition of KRT8 phosphorylation serve to inhibit oxidative stress-induced EMT of RPE cells as well as to prevent cell death, suggesting that pharmacological manipulation of KRT8 upregulation through autophagy with combined inhibition of the MAPK1/3 pathway may be attractive therapeutic strategies for the treatment of AMD. 相似文献
240.
Manalo DJ Baek JH Buehler PW Struble E Abraham B Alayash AI 《Biochemical and biophysical research communications》2011,416(3-4):421-426