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排序方式: 共有272条查询结果,搜索用时 15 毫秒
51.
Katja Fischer Christopher G. Langendorf James A. Irving Simone Reynolds Charlene Willis Ruby H.P. Law Tanya A. Bashtannyk-Puhalovich James C. Whisstock Robert N. Pike Ashley M. Buckle 《Journal of molecular biology》2009,390(4):635-645
The scabies mite (Sarcoptes scabiei) is a parasite responsible for major morbidity in disadvantaged communities and immuno-compromised patients worldwide. In addition to the physical discomfort caused by the disease, scabies infestations facilitate infection by Streptococcal species via skin lesions, resulting in a high prevalence of rheumatic fever/heart disease in affected communities. The scabies mite produces 33 proteins that are closely related to those in the dust mite group 3 allergen and belong to the S1-like protease family (chymotrypsin-like). However, all but one of these molecules contain mutations in the conserved active-site catalytic triad that are predicted to render them catalytically inactive. These molecules are thus termed scabies mite inactivated protease paralogues (SMIPPs). The precise function of SMIPPs is unclear; however, it has been suggested that these proteins might function by binding and protecting target substrates from cleavage by host immune proteases, thus preventing the host from mounting an effective immune challenge. In order to begin to understand the structural basis for SMIPP function, we solved the crystal structures of SMIPP-S-I1 and SMIPP-S-D1 at 1.85 Å and 2.0 Å resolution, respectively. Both structures adopt the characteristic serine protease fold, albeit with large structural variations over much of the molecule. In both structures, mutations in the catalytic triad together with occlusion of the S1 subsite by a conserved Tyr200 residue is predicted to block substrate ingress. Accordingly, we show that both proteases lack catalytic function. Attempts to restore function (via site-directed mutagenesis of catalytic residues as well as Tyr200) were unsuccessful. Taken together, these data suggest that SMIPPs have lost the ability to bind substrates in a classical “canonical” fashion, and instead have evolved alternative functions in the lifecycle of the scabies mite. 相似文献
52.
Marland Z Beddoe T Zaker-Tabrizi L Lucet IS Brammananth R Whisstock JC Wilce MC Coppel RL Crellin PK Rossjohn J 《Journal of molecular biology》2006,359(4):983-997
The waxy cell wall is crucial to the survival of mycobacteria within the infected host. The cell wall is a complex structure rich in unusual molecules that includes two related lipoglycans, the phosphatidylinositol mannosides (PIMs) and lipoarabinomannans (LAMs). Many proteins implicated in the PIM/LAM biosynthetic pathway, while attractive therapeutic targets, are poorly defined. The 2.4A resolution crystal structure of an essential lipoprotein, LpqW, implicated in LAM biosynthesis is reported here. LpqW adopts a scaffold reminiscent of the distantly related, promiscuous substrate-binding proteins of the ATP-binding cassette import system. Nevertheless, the unique closed conformation of LpqW suggests that mycobacteria and other closely related pathogens have hijacked this scaffold for use in key processes of cell wall biosynthesis. In silico docking provided a plausible model in which the candidate PIM ligand binds within a marked electronegative region located on the surface of LpqW. We suggest that LpqW represents an archetypal lipoprotein that channels intermediates from a pathway for mature PIM production into a pathway for LAM biosynthesis, thus controlling the relative abundance of these two important components of the cell wall. 相似文献
53.
Christopher G. Langendorf Trevor L. G. Key Gustavo Fenalti Wan-Ting Kan Ashley M. Buckle Tom Caradoc-Davies Kellie L. Tuck Ruby H. P. Law James C. Whisstock 《PloS one》2010,5(2)
Background
In mammals succinic semialdehyde dehydrogenase (SSADH) plays an essential role in the metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) to succinic acid (SA). Deficiency of SSADH in humans results in elevated levels of GABA and γ-Hydroxybutyric acid (GHB), which leads to psychomotor retardation, muscular hypotonia, non-progressive ataxia and seizures. In Escherichia coli, two genetically distinct forms of SSADHs had been described that are essential for preventing accumulation of toxic levels of succinic semialdehyde (SSA) in cells.Methodology/Principal Findings
Here we structurally characterise SSADH encoded by the E coli gabD gene by X-ray crystallographic studies and compare these data with the structure of human SSADH. In the E. coli SSADH structure, electron density for the complete NADP+ cofactor in the binding sites is clearly evident; these data in particular revealing how the nicotinamide ring of the cofactor is positioned in each active site.Conclusions/Significance
Our structural data suggest that a deletion of three amino acids in E. coli SSADH permits this enzyme to use NADP+, whereas in contrast the human enzyme utilises NAD+. Furthermore, the structure of E. coli SSADH gives additional insight into human mutations that result in disease. 相似文献54.
Amin AA Faux NG Fenalti G Williams G Bernadou A Daglish B Keefe K Middleton S Rae J Tetis K Law RH Fulton KF Rossjohn J Whisstock JC Buckle AM 《Proteins》2006,62(1):4-7
The crystallization of macromolecules remains a major bottleneck in structural biology. The routine screening of more than one thousand crystallization conditions and subsequent optimization by fine screening presents a challenge to conventional laboratory notebook keeping. In addition, the development of high-throughput robotic crystallization and imaging systems presents a pressing need for low-cost laboratory information management system (LIMS). Here we describe CLIMS2, a crystallization LIMS that features a simple, user-friendly graphical interface, allowing the storage, management, retrieval and mining of crystallization data. The CLIMS2 executable and documentation is freely available at http://clims.med.monash.edu.au. 相似文献
55.
Sarah E. Stewart Catherina H. Bird Rico F. Tabor Michael E. D'Angelo Stefania Piantavigna James C. Whisstock Joseph A. Trapani Lisandra L. Martin Phillip I. Bird 《The Journal of biological chemistry》2015,290(52):31101-31112
Perforin is an essential component in the cytotoxic lymphocyte-mediated cell death pathway. The traditional view holds that perforin monomers assemble into pores in the target cell membrane via a calcium-dependent process and facilitate translocation of cytotoxic proteases into the cytoplasm to induce apoptosis. Although many studies have examined the structure and role of perforin, the mechanics of pore assembly and granzyme delivery remain unclear. Here we have employed quartz crystal microbalance with dissipation monitoring (QCM-D) to investigate binding and assembly of perforin on lipid membranes, and show that perforin monomers bind to the membrane in a cooperative manner. We also found that cholesterol influences perforin binding and activity on intact cells and model membranes. Finally, contrary to current thinking, perforin efficiently binds membranes in the absence of calcium. When calcium is added to perforin already on the membrane, the QCM-D response changes significantly, indicating that perforin becomes membranolytic only after calcium binding. 相似文献
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59.
Molecular evolution of mitochondrial 12S RNA and cytochrome b sequences in the pantherine lineage of Felidae 总被引:4,自引:2,他引:2
DNA sequence comparisons of two mitochondrial DNA genes were used to infer
phylogenetic relationships among 17 Felidae species, notably 15 in the
previously described pantherine lineage. The polymerase chain reaction
(PCR) was used to generate sequences of 358 base pairs of the mitochondrial
12S RNA gene and 289 base pairs of the cytochrome b protein coding gene.
DNA sequences were compared within and between 17 felid and five nonfelid
carnivore species. Evolutionary trees were constructed using phenetic,
cladistic, and maximum likelihood algorithms. The combined results
suggested several phylogenetic relationships including (1) the recognition
of a recently evolved monophyletic genus Panthera consisting of Panthera
leo, P. pardus, P. onca, P. uncia, P. tigris, and Neofelis nebulosa; (2)
the recent common ancestry of Acinonyx jubatus, the African cheetah, and
Puma concolor, the American puma; and (3) two golden cat species, Profelis
temmincki and Profelis aurata, are not sister species, and the latter is
strongly associated with Caracal caracal. These data add to the growing
database of vertebrate mtDNA sequences and, given the relatively recent
divergence among the felids represented here (1-10 Myr), allow 12S and
cytochrome b sequence evolution to be addressed over a time scale different
from those addressed in most work on vertebrate mtDNA.
相似文献
60.
Sea urchin Hox genes: insights into the ancestral Hox cluster 总被引:3,自引:0,他引:3
We describe the Hox cluster in the radially symmetric sea urchin and
compare our findings to what is known from clusters in bilaterally
symmetric animals. Several Hox genes from the direct-developing sea urchin
Heliocidaris erythrogramma are described. CHEF gel analysis shows that the
Hox genes are clustered on a < or = 300 kilobase (kb) fragment of DNA,
and only a single cluster is present, as in lower chordates and other
nonvertebrate metazoans. Phylogenetic analyses of sea urchin, amphioxus,
Drosophila, and selected vertebrate Hox genes confirm that the H.
erythrogramma genes, and others previously cloned from other sea urchins,
belong to anterior, central, and posterior groups. Despite their radial
body plan and lack of cephalization, echinoderms retain at least one of the
anterior group Hox genes, an orthologue of Hox3. The structure of the
echinoderm Hox cluster suggests that the ancestral deuterostome had a Hox
cluster more similar to the current chordate cluster than was expected Sea
urchins have at least three Abd-B type genes, suggesting that Abd-B
expansion began before the radiation of deuterostomes.
相似文献