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Induced fit in guanidino kinases--comparison of substrate-free and transition state analog structures of arginine kinase 总被引:1,自引:0,他引:1 下载免费PDF全文
Yousef MS Clark SA Pruett PK Somasundaram T Ellington WR Chapman MS 《Protein science : a publication of the Protein Society》2003,12(1):103-111
Arginine kinase (AK) is a member of the guanidino kinase family that plays an important role in buffering ATP concentration in cells with high and fluctuating energy demands. The AK specifically catalyzes the reversible phosphoryl transfer between ATP and arginine. We have determined the crystal structure of AK from the horseshoe crab (Limulus polyphemus) in its open (substrate-free) form. The final model has been refined at 2.35 A with a final R of 22.3% (R(free) = 23.7%). The structure of the open form is compared to the previously determined structure of the transition state analog complex in the closed form. Classically, the protein would be considered two domain, but dynamic domain (DynDom) analysis shows that most of the differences between the two structures can be considered as the motion between four rigid groups of nonsequential residues. ATP binds near a cluster of positively charged residues of a fixed dynamic domain. The other three dynamic domains close the active site with separate hinge rotations relative to the fixed domain. Several residues of key importance for the induced motion are conserved within the phosphagen kinase family, including creatine kinase. Substantial conformational changes are induced in different parts of the enzyme as intimate interactions are formed with both substrates. Thus, although induced fit occurs in a number of phosphoryl transfer enzymes, the conformational changes in phosphagen kinases appear to be more complicated than in prior examples. 相似文献
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The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents 总被引:8,自引:0,他引:8
Lubetsky JB Dios A Han J Aljabari B Ruzsicska B Mitchell R Lolis E Al-Abed Y 《The Journal of biological chemistry》2002,277(28):24976-24982
Macrophage migration inhibitory factor (MIF) is an immunoregulatory protein that is a potential therapeutic target for a number of inflammatory diseases. Evidence exists that an unexpected catalytic active site of MIF may have a biological function. To gain further insight into the role of the catalytic active site, a series of mutational, structural, and biological activity studies were performed. The insertion of an alanine between Pro-1 and Met-2 (PAM) abolishes a non-physiological catalytic activity, and this mutant is defective in the in vitro glucocorticoid counter-regulatory activity of MIF. The crystal structure of MIF complexed to (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), an inhibitor of MIF d-dopachrome tautomerase activity, reveals that ISO-1 binds to the same position of the active site as p-hydroxyphenylpyruvic acid, a substrate of MIF. ISO-1 inhibits several MIF biological activities, further establishing a role for the catalytic active site of MIF. 相似文献
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AIMS: To develop a non-competitive direct immunoassay method for quantifying nisin in solution or adsorbed to surfaces. METHODS AND RESULTS: The developed method differs from traditional ELISA in pre-forming a complex of the nisin antibodies and the secondary antibody conjugate before addition to the nisin-coated solid phase. The modifications may help decrease interference from the nisin degradation molecules and reduce non-specific adsorption of secondary antibody conjugate. The new method has a detection limit of 65 ng nisin and correlates well (r=0.982) with the agar diffusion bioassay. CONCLUSIONS: A new sensitivity method was developed to determine the amounts of nisin adsorbed to a polymeric surface. SIGNIFICANCE AND IMPACT OF THE STUDY: The new technique can provide a reproducible and accurate method to quantitate nisin molecules in solutions and those bound on polymeric surfaces, and it is free of the limitations of the traditional agar diffusion bioassay. 相似文献
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The expanded human kallikrein gene family: locus characterization and molecular cloning of a new member, KLK-L3 (KLK9) 总被引:3,自引:0,他引:3
In rodents, kallikreins are encoded by a large multigene family but in humans, only three kallikrein genes were thought to exist. Based on the homology between the human and the rodent kallikrein loci, we defined a 300-kb human kallikrein gene region on chromosome 19q13. 3-q13.4. By using linear sequence information, restriction analysis, PCR, and blotting techniques, we were able to construct the first detailed map of the human kallikrein gene locus. Comparative analysis of genes located in this area enabled us to expand the human kallikrein multigene family with some recently identified serine proteases and establish common structural features. We further identified a new kallikrein-like gene, named kallikrein-like gene 3 (KLK-L3; HGMW-approved symbol KLK9). We describe the structural characterization of the KLK-L3 gene, together with its precise chromosomal localization in relation to other kallikreins and its tissue expression pattern and hormonal regulation. 相似文献
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Foussias G Yousef GM Diamandis EP 《Biochemical and biophysical research communications》2000,278(3):775-781
Through efforts to investigate the CD33-like subgroup of sialic acid binding immunoglobulin-like lectins (Siglecs), which are believed to be located on chromosome 19q13.4, we have identified the precise genomic region containing the Siglec8 gene. It is located on chromosome 19q13.4, approximately 330 kb downstream of the Siglec9 gene. Further, we have identified a novel Siglec8 variant, named Siglec8-Long (Siglec8-L), which differs in its last two exons from the previously published mRNA sequence of Siglec8 (GenBank Accession No. AF195092). Both Siglec8 and Siglec8-L are comprised of seven exons, of which the first five are identical, followed by marked differences in exon usage and mRNA splicing. The 499 amino acid protein encoded by the Siglec8-L open reading frame has a molecular weight of 54 kDa. Like the other members of the CD33-like subgroup of Siglecs, except for the previously published Siglec8, Siglec8-L also contains the two tyrosine-based motifs that have been found to recruit both SH2 domain-containing tyrosine and inositol phosphatases. 相似文献