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Sökning: WFRF:(Thunnissen MMGM)

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  • Uysal, Hüseyin, et al. (författare)
  • Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis.
  • 2009
  • Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 206:2, s. 449-462
  • Tidskriftsartikel (refereegranskat)abstract
    • Antibodies to citrulline-modified proteins have a high diagnostic value in rheumatoid arthritis (RA). However, their biological role in disease development is still unclear. To obtain insight into this question, a panel of mouse monoclonal antibodies was generated against a major triple helical collagen type II (CII) epitope (position 359-369; ARGLTGRPGDA) with or without arginines modified by citrullination. These antibodies bind cartilage and synovial tissue, and mediate arthritis in mice. Detection of citrullinated CII from RA patients' synovial fluid demonstrates that cartilage-derived CII is indeed citrullinated in vivo. The structure determination of a Fab fragment of one of these antibodies in complex with a citrullinated peptide showed a surprising beta-turn conformation of the peptide and provided information on citrulline recognition. Based on these findings, we propose that autoimmunity to CII, leading to the production of antibodies specific for both native and citrullinated CII, is an important pathogenic factor in the development of RA.
  • Andersson, B, et al. (författare)
  • Crystallization and X-ray diffraction data analysis of leukotriene A4 hydrolase from Saccharomyces cerevisiae
  • 2003
  • Ingår i: Acta Crystallographica. Section D: Biological Crystallography. - : John Wiley and Sons. - 1399-0047. ; 59:Pt 6, s. 1093-1095
  • Tidskriftsartikel (refereegranskat)abstract
    • The Saccharomyces cerevisiae leukotriene A4 (LTA4) hydrolase (scLTA4 hydrolase) has been crystallized in order to study the two activities of LTA4 hydrolase in an evolutionary perspective. Single well diffracting crystals are obtained after switching from the hanging-drop method to liquid-liquid diffusion in capillaries using PEG 8000 as precipitant. These crystals belong to space group P212121, with unit-cell parameters a = 70.8, b = 98.1, c = 99.2 Å. Intensity data to 2.3 Å resolution were collected from a native scLTA4 hydrolase crystal using synchrotron radiation. A molecular-replacement solution was obtained using the human LTA4 hydrolase structure and the program BEAST.
  • Tholander, F, et al. (författare)
  • Leukotriene A4 Hydrolase, Insights into the Molecular Evolution by Homology Modeling and Mutational Analysis of Enzyme from Saccharomyces cerevisiae
  • 2005
  • Ingår i: Journal of Biological Chemistry. - : ASBMB. - 1083-351X .- 0021-9258. ; 280:39, s. 33477-33486
  • Tidskriftsartikel (refereegranskat)abstract
    • Mammalian leukotriene A4 (LTA4) hydrolase is a bifunctional zinc metalloenzyme possessing an Arg/Ala aminopeptidase and an epoxide hydrolase activity, which converts LTA4 into the chemoattractant LTB4. We have previously cloned an LTA4 hydrolase from Saccharomyces cerevisiae with a primitive epoxide hydrolase activity and a Leu aminopeptidase activity, which is stimulated by LTA4. Here we used a modeled structure of S. cerevisiae LTA4 hydrolase, mutational analysis, and binding studies to show that Glu-316 and Arg-627 are critical for catalysis, allowing us to a propose a mechanism for the epoxide hydrolase activity. Guided by the structure, we engineered S. cerevisiae LTA4 hydrolase to attain catalytic properties resembling those of human LTA4 hydrolase. Thus, six consecutive point mutations gradually introduced a novel Arg aminopeptidase activity and caused the specific Ala and Pro aminopeptidase activities to increase 24 and 63 times, respectively. In contrast to the wild type enzyme, the hexuple mutant was inhibited by LTA4 for all tested substrates and to the same extent as for the human enzyme. In addition, these mutations improved binding of LTA4 and increased the relative formation of LTB4, whereas the turnover of this substrate was only weakly affected. Our results suggest that during evolution, the active site of an ancestral eukaryotic zinc aminopeptidase has been reshaped to accommodate lipid substrates while using already existing catalytic residues for a novel, gradually evolving, epoxide hydrolase activity. Moreover, the unique ability to catalyze LTB4 synthesis appears to be the result of multiple and subtle structural rearrangements at the catalytic center rather than a limited set of specific amino acid substitutions.
  • Tholander, Fredrik, et al. (författare)
  • Structure-Based Dissection of the Active Site Chemistry of Leukotriene A4 Hydrolase: Implications for M1 Aminopeptidases and Inhibitor Design
  • 2008
  • Ingår i: Chemistry and Biology. - : Cell Press. - 1879-1301 .- 1074-5521. ; 15:9, s. 920-929
  • Tidskriftsartikel (refereegranskat)abstract
    • M1 aminopeptidases comprise a large family of biologically important zinc enzymes. We show that peptide turnover by the M1 prototype, leukotriene A4 hydrolase/aminopeptidase, involves a shift in substrate position associated with exchange of zinc coordinating groups, while maintaining the overall coordination geometry. The transition state is stabilized by residues conserved among M1 members and in the final reaction step, Glu-296 of the canonical zinc binding HEXXH motif shuffles a proton from the hydrolytic water to the leaving group. Tripeptide substrates bind along the conserved GXMEN motif, precisely occupying the distance between Glu-271 and Arg-563, whereas the Arg specificity is governed by a narrow S1 pocket capped with Asp-375. Our data provide detailed insights to the active site chemistry of M1 aminopeptidases and will aid in the development of novel enzyme inhibitors.
  • Haeggstrom, JZ, et al. (författare)
  • Leukotriene A4 hydrolase
  • 2002
  • Ingår i: Prostaglandins & other lipid mediators. - 1098-8823. ; 68-968-69, s. 495-510
  • Tidskriftsartikel (refereegranskat)
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  • Resultat 1-10 av 12
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