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1.
Crystallization and preliminary x-ray diffraction studies of two new antigen-antibody (lysozyme-Fab) complexes 总被引:2,自引:0,他引:2
T Fischmann H Souchon M M Riottot D Tello R J Poljak 《Journal of molecular biology》1988,203(2):527-529
The complexes between the Fab fragments of two monoclonal anti-lysozyme antibodies, Fab10.6.6 (high affinity) and D44.2 (lower affinity), and their specific antigen, hen egg-white lysozyme, have been crystallized. The antibodies recognize an antigenic determinant including Arg68, but differ significantly in their association constants for the antigen. Two crystalline forms were obtained for the complex with FabF10.6.6, the higher affinity antibody. One of them is monoclinic, space group P21, with unit cell dimensions a = 145.6 A, b = 78.1 A, c = 63.1 A, beta = 89.05 degrees, consistent with the presence of two molecules of the complex in the asymmetric unit. These crystals diffract X-rays beyond 3 A making this form suitable for high-resolution X-ray diffraction studies. The second form crystallizes in the triclinic space group P1, with unit cell dimensions a = 134.0 A, b = 144.7 A, c = 98.6 A, alpha = 90.30 degrees, beta = 97.1 degrees, gamma = 90.20 degrees, consistent with the presence of 10 to 12 molecules of the complex in the unit cell. These crystals do not diffract X-rays beyond 5 A resolution. The antigen-antibody complex between FabD44.2, the lower affinity antibody, and hen egg-white lysozyme crystallizes in space group P2(1)2(1)2(1), with unit cell dimensions a = 99.7 A, b = 167.3 A, c = 84.7 A, consistent with the presence of two molecules of the complex in the asymmetric unit. These crystals diffract X-rays beyond 2.5 A resolution. 相似文献
2.
Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation 总被引:4,自引:0,他引:4
Fischmann TO Hruza A Niu XD Fossetta JD Lunn CA Dolphin E Prongay AJ Reichert P Lundell DJ Narula SK Weber PC 《Nature structural biology》1999,6(3):233-242
Crystal structures of human endothelial nitric oxide synthase (eNOS) and human inducible NOS (iNOS) catalytic domains were solved in complex with the arginine substrate and an inhibitor S-ethylisothiourea (SEITU), respectively. The small molecules bind in a narrow cleft within the larger active-site cavity containing heme and tetrahydrobiopterin. Both are hydrogen-bonded to a conserved glutamate (eNOS E361, iNOS E377). The active-site residues of iNOS and eNOS are nearly identical. Nevertheless, structural comparisons provide a basis for design of isozyme-selective inhibitors. The high-resolution, refined structures of eNOS (2.4 A resolution) and iNOS (2.25 A resolution) reveal an unexpected structural zinc situated at the intermolecular interface and coordinated by four cysteines, two from each monomer. 相似文献
3.
Vinod R. Hegde Scott Borges Haiyan Pu Mahesh Patel Vincent P. Gullo Bonnie Wu Paul Kirschmeier Michael J. Williams Vincent Madison Thierry Fischmann Tze-Ming Chan 《Bioorganic & medicinal chemistry letters》2010,20(4):1384-1387
Several analogs of aristolochic acids were isolated and derivatized into their lactam derivatives to study their inhibition in CDK2 assay. The study helped to derive some conclusions about the structure–activity relation around the phenanthrin moiety. Semi-synthetic aristolactam 21 showed good activity with inhibition IC50 of 35 nM in CDK2 assay. The activity of this compound was comparable to some of the most potent synthetic compounds reported in the literature. 相似文献
4.
Labroli M Paruch K Dwyer MP Alvarez C Keertikar K Poker C Rossman R Duca JS Fischmann TO Madison V Parry D Davis N Seghezzi W Wiswell D Guzi TJ 《Bioorganic & medicinal chemistry letters》2011,21(1):471-474
Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors. 相似文献
5.
TO Sogbanmu AO Osibona OA Oguntunde AA Otitoloju 《African Journal of Aquatic Science》2018,43(3):281-292
Physiological, biochemical and histological indices in Clarias gariepinus broodstock, and teratogenic indices in embryos exposed to sublethal concentrations of naphthalene, phenanthrene and pyrene were investigated in 2014 using a static-renewal bioassay protocol. Phenanthrene (1.41 mg l?1) was the most toxic, followed by pyrene (1.53 mg l?1) and naphthalene (7.21 mg l?1), based on 96 h LC50 values. Hepatosomatic indices were significantly higher in naphthalene- and pyrene-treated males compared with solvent controls, whereas fecundity in females was significantly lower by factors of 2.4 (naphthalene), 2.8 (phenanthrene) and 2.4 (pyrene), compared with controls. Catalase levels were lower in female phenanthrene-treated fish compared with controls. Histological alterations observed in PAH-treated fish include oedema, inflammatory cells, epithelial lifting and hyperplasia in the gills, vacuolation, haemosiderin pigments and sinusoidal congestion in the liver, and degenerated zona radiata in the ovary. Teratogenic effects were not observed, as evidenced by the lack of histological alterations in embryos spawned from pre-exposed broodstock. Sex-specific responses and the utility of biomarkers at cellular and individual levels of organisation are therefore demonstrated for holistic evaluations of polycyclic aromatic hydrocarbons in ecotoxicological studies. 相似文献
6.
Graham F. Smith Michael D. Altman Brian Andresen James Baker Jason D. Brubaker Hongmin Chen Yiping Chen Matthew Childers Anthony Donofrio Heidi Ferguson Christian Fischer Thierry O. Fischmann Craig Gibeau Alexander Hicks Sue Jin Sam Kattar Melanie A. Kleinschek Erica Leccese Alan Northrup 《Bioorganic & medicinal chemistry letters》2017,27(12):2721-2726
Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation. 相似文献
7.
PAULO M. FARIA E SILVA ANTONIO M. SOLÉ-CAVA MAURILIO J. SOARES MARIA CRISTINA M. MOTTA JOÁTO E. FIORINI WANDERLEY DE SOUZA 《The Journal of eukaryotic microbiology》1991,38(5):489-494
The trypanosomatid previously described as Crithidia roitmani is characterized here at the ultrastructural and biochemical levels. The data indicates that the parasite belongs to the Herpetomonas genus, and we therefore suggest the flagellate to be denominated as Herpetomonas roitmani n. comb. Cladistic analysis of isoenzyme data generated by eight different enzymes showed that the parasite presented a distinct banding pattern and could be grouped with some Herpetomonas spp., but not with Crithidia spp., used as reference strains. Accordingly, when the parasites were grown for longer periods in Roitman's defined medium, expontaneous differentiation from promastigotes to opisthomastigotes (typical of the Herpetomonas genus) occurred. Transmission electron microscopy revealed the presence of bacterium-like endosymbionts in the cytoplasm of all evolutive forms of the parasite. All morphological alterations characteristic of endosymbiont-bearing trypanosomatids could be observed. 相似文献
8.
9.
G A Bentley P M Alzari A G Amit G Boulot V Guillon-Chitarra T Fischmann M B Lascombe R A Mariuzza R J Poljak M M Riottot 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》1989,323(1217):487-494
By using X-ray diffraction and immunochemical techniques, we have exploited the use of monoclonal antibodies raised against hen egg lysozyme (HEL) to study systematically those factors responsible for the high specificity of antigen-antibody interactions. HEL was chosen for our investigations because its three-dimensional structure and immunochemistry have been well characterized and because naturally occurring sequence variants from different avian species are readily available to test the fine specificity of the antibodies. The X-ray crystal structure of a complex formed between HEL and the Fab D1.3 shows a large complementary surface with close interatomic contacts between antigen and antibody. Thus single amino acid sequence changes in heterologous antigens give antigen-antibody association constants that are several orders of magnitude smaller than that of the homologous antigen. For example, a substitution of His for Glu at position 121 in the antigen is sufficient to diminish significantly the binding between D1.3 and the variant lysozyme. The conformation of HEL when complexed to D1.3 shows no significant difference from that seen in the free molecule, and immunobinding studies with other anti-HEL antibodies suggest that this observation may be generally true for the system of monoclonal antibodies that we have studied. 相似文献
10.
Michael P. Dwyer Kartik Keertikar Kamil Paruch Carmen Alvarez Marc Labroli Cory Poker Thierry O. Fischmann Rosemary Mayer-Ezell Richard Bond Yan Wang Rita Azevedo Timothy J. Guzi 《Bioorganic & medicinal chemistry letters》2013,23(22):6178-6182
The synthesis and hit-to-lead SAR development from a pyrazolo[1,5-a]pyrimidine-derived hit 5 to the identification of a series of potent, pan–Pim inhibitors such as 11j are described. 相似文献