Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hoffmaster et al. [Hoffmaster AR, Ravel J, Rasko DA, Chapman GD, Chute MD, Marston CK, et al. Identification of anthrax toxin genes in Bacillus cereus associated with illness resembling inhalation anthrax. Proc Natl Acad Sci U S A 2004;101:8449-54; Hoffmaster AR, Hill KK, Gee JE, Marston CK, De BK, Popovic T, et al. Characterization of Bacillus cereus isolates associated with fatal pneumonias: strains are closely related to Bacillus anthracis and harbor B. anthracis virulence genes. J Clin Microbiol 2006;44:3352-60] phylogenetically divided Bacillus cereus strains into 10 branches by amplified fragment length polymorphism (AFLP) with Branch F including all Bacillus anthracis strains and pneumonia-causing strains of B. cereus. There are four sub-branches within Branch F, referred to here as F1-A, F1-B, F2-A and F2-B. The B. anthracis strains are found within sub-branch F1-B. Concerning, the currently available B. cereus pneumonia-causing isolates, one was found to categorize within sub-branch F1-B and two within F2-B. In the following work the sequence variation between B. cereus strains was determined by MALDI-TOF MS and MS-MS for each strain of B. cereus in Branch F. ESI-MS was performed on selected strains for confirmation. Small acid-soluble proteins (SASPs) of B. cereus strains found in F1-B showed a single amino acid substitution, while strains in the other three sub-branches were more variable generally showing one or two amino acid substitutions. The single substitutions always occurred in the C-terminus. Double substitutions occurred in both N and C termini. Of the pneumonia-causing strains, one exhibited a single amino acid substitution, while the other two exhibited a two amino acid substitution.
Mol Cell Probes 2008 Jun
PMID:The Bacillus cereus containing sub-branch most closely related to Bacillus anthracis, have single amino acid substitutions in small acid-soluble proteins, while remaining sub-branches are more variable. 1843 62

Anthrax lethal toxin (LeTx) shows potent mitogen-activated protein kinase pathway inhibition and apoptosis in melanoma cells that harbor the activating V600E B-RAF mutation. LeTx is composed of two proteins, protective antigen and lethal factor. Uptake of the toxin into cells is dependent on proteolytic activation of protective antigen by the ubiquitously expressed furin or furin-like proteases. To circumvent nonspecific LeTx activation, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. Here, we have shown that the toxicity of this matrix metalloproteinase (MMP)-activated LeTx is dependent on host cell surface MMP-2 and MMP-9 activity as well as the presence of the activating V600E B-RAF mutation, making this toxin dual specific. This additional layer of tumor cell specificity would potentially decrease systemic toxicity from the reduction of nonspecific toxin activation while retaining antitumor efficacy in patients with V600E B-RAF melanomas. Moreover, our results indicate that cell surface-associated gelatinase expression can be used to predict sensitivity among V600E B-RAF melanomas. This finding will aid in the better selection of patients that will potentially respond to MMP-activated LeTx therapy.
Mol Cancer Ther 2008 May
PMID:Cytotoxicity of the matrix metalloproteinase-activated anthrax lethal toxin is dependent on gelatinase expression and B-RAF status in human melanoma cells. 1848 9

Flock House virus (FHV) is a nonenveloped, icosahedral insect virus whose genome consists of two molecules of single-stranded, positive-sense RNA. FHV is a highly tractable system for studies on a variety of basic aspects of RNA virology. In this review, recent studies on the replication of FHV genomic and subgenomic RNA are discussed, including a landmark study on the ultrastructure and molecular organization of FHV replication complexes. In addition, we show how research on FHV B2, a potent suppressor of RNA silencing, resulted in significant insights into antiviral immunity in insects. We also explain how the specific packaging of the bipartite genome of this virus is not only controlled by specific RNA-protein interactions but also by coupling between RNA replication and genome recognition. Finally, applications for FHV as an epitopepresenting system are described with particular reference to its recent use for the development of a novel anthrax antitoxin and vaccine.
Cell Mol Life Sci 2008 Sep
PMID:Recent insights into the biology and biomedical applications of Flock House virus. 1851 98

We analyzed the 440-kDa transmembrane pore formed by the protective antigen (PA) moiety of anthrax toxin in the presence of GroEL by negative-stain electron microscopy. GroEL binds both the heptameric PA prepore and the PA pore. The latter interaction retards aggregation of the pore, prolonging its insertion-competent state. Two populations of unaggregated pores were visible: GroEL-bound pores and unbound pores. This allowed two virtually identical structures to be reconstructed, at 25-A and 28-A resolution, respectively. The structures were mushroom-shaped objects with a 125-A-diameter cap and a 100-A-long stem, consistent with earlier biochemical data. Thus, GroEL provides a platform for obtaining initial glimpses of a membrane protein structure in the absence of lipids or detergents and can function as a scaffold for higher-resolution structural analysis of the PA pore.
Nat Struct Mol Biol 2008 Jul
PMID:GroEL as a molecular scaffold for structural analysis of the anthrax toxin pore. 1856 38

Specific identification of Bacillus anthracis and differentiation from closely related Bacillus cereus and Bacillus thuringiensis strains is still a major diagnostic problem. Commercially available diagnostic kits targeting plasmid-markers cannot differentiate between B. anthracis, non-anthracis Bacillus species harbouring anthrax-specific virulence plasmids, and plasmidless B. anthracis strains. A TaqMan PCR assay was designed targeting sequences of gene locus BA_5345 of the B. anthracis strain Ames. Specificity was determined by using a panel of 328 Bacillus strains; sensitivity was determined by probit analysis. All B. anthracis isolates (n=92) were specifically detected by using the genomic TaqMan PCR assay whereas 236 strains belonging to 19 Bacillus species other than B. anthracis were PCR negative. The detection limit was determined to be 12.7 copies per reaction (95% confidence interval 10.2-17.5 copies). Here we present an extensively evaluated and - to our current knowledge - specific TaqMan PCR assay for the detection of B. anthracis based on a chromosomal marker.
Mol Cell Probes
PMID:Real-time PCR system targeting a chromosomal marker specific for Bacillus anthracis. 1860 86

Bacterial agents or products more likely to be used as biological weapons of mass destruction are Bacillus anthracis, Francisella tularensis, Yersinia pestis, and the neurotoxin of Clostridium botulinum. Anthrax is an acute infectious disease with a high mortality rate caused by Bacillus anthracis, reinforcing the need for better adjunctive therapy and prevention strategies. In this paper, we developed 7 QSAR models on penicillin-based inhibitors of the class A and B beta-lactamases from B. anthracis and inhibitors of anthrax lethal factor to understand the chemical-biological interactions. Hydrophobic and steric factors are found to be the most important determinants of the activity. Internal (cross-validation ( q (2)), quality factor ( Q), Fischer statistics ( F), and Y-randomization) and external validation tests have validated all the QSAR models.
Mol Pharm
PMID:Combating the threat of anthrax: a quantitative structure-activity relationship approach. 1861 Oct 38

Anthrax receptor (ATR) shares similarities with molecules relevant to haematopoiesis. This suggests that anthrax proteins might bind to these mimicking molecules and exert non-specific haematopoietic effects. The haematopoietic system is the site of immune cell development in the adult. As such, ATR ligand, protective antigen (PA) and the other anthrax proteins, lethal factor, edema factor, could be significant to haematopoietic responses against Bacillus anthracis infection. Because haematopoiesis is the process of immune cell development, effects by anthrax proteins could be relevant to vaccine development. Here, we report on effects of anthrax proteins and toxins on early and late haematopoiesis. Flow cytometry shows binding of PA to haematopoietic cells. This binding might be partly specific because flow cytometry and Western blots demonstrate the presence of ATR1 on haematopoietic cell subsets and the supporting stromal cells. Functional studies with long-term initiating cell and clonogenic assays determined haematopoietic suppression by anthrax toxins and stimulation by monomeric proteins. The suppressive effects were not attributed to cell death, but partly through the induction of haematopoietic suppressors, interleukin (IL)-10 and CCL3 (MIP-1alpha). In summary, anthrax proteins affect immune cell development by effects on haematopoiesis. The type of effect, stimulation or suppression, depend on whether the stimulator is a toxin or monomeric protein. The studies show effects of anthrax proteins beginning at the early stage of haematopoiesis, and also show secondary mediators such as IL-10 and CCL3. The roles of other cytokines and additional ATR are yet to be investigated.
J Cell Mol Med 2009 Aug
PMID:Non-canonical effects of anthrax toxins on haematopoiesis: implications for vaccine development. 1875 38

Fab 35PA83 is an antibody fragment of non-human primate origin that neutralizes the anthrax lethal toxin. Human antibodies are usually preferred when clinical use is envisioned, even though their framework regions (FR) may carry mutations introduced during affinity maturation. These hypermutations can be immunogenic and therefore FR that are encoded by human germline genes, encountered in IgMs and thus part of the "self" proteins, are preferable. Accordingly, the proportion of FR residues in 35PA83 that were encoded by human V and J germline genes, i.e. the germinality index (GI) of 35PA83, was increased in a multistep cumulative approach. In a first step, the FR1 and FR4 residues of 35PA83 were changed simultaneously into their counterparts coded by 35PA83's closest human germline genes, without prior modelling. The resulting derivative of 35PA83 had the same affinity as its parental Fab. In a second step, the 3D structures of this first 35PA83 derivative, carrying the same type of residue changes but in the FR2 and FR3 regions, were modelled in silico from sequences. Some of the changes in FR2 or FR3 modified the predicted peptide backbone. The changes that did not seem to alter the structure were introduced simultaneously in the Fab by an in vitro method and resulted in a loss of reactivity, which could however be fully restored by a single point mutation. The final 35PA83 derivative had a GI higher than that of a fully human Fab, which had neutralization properties similar to 35PA83 and which was used as a benchmark in this study.
J Mol Biol 2008 Dec 31
PMID:Germline humanization of a non-human primate antibody that neutralizes the anthrax toxin, by in vitro and in silico engineering. 1897 62

Bacillus anthracis represents a formidable bioterrorism and biowarfare threat for which new vaccines are needed with improved safety and efficacy over current options. Toward this end, we created recombinant adeno-associated virus type 1 (rAAV1) vectors containing synthetic genes derived from the protective antigen (PA) or lethal factor (LF) of anthrax lethal toxin (LeTx) and tested them for immunogenicity and induction of toxin-neutralizing antibodies in rabbits. Codon-optimized segments encoding activated PA (PA63), or LF, were synthesized and cloned into optimized rAAV1 vectors containing a human cytomegalovirus (hCMV) promoter and synthetic optimized leader. Serum from rabbits immunized intramuscularly with rAAV1/PA (monovalent), rAAV1/LF (monovalent), rAAV1/PA + rAAV1/LF (bivalent), or rAAV1/enhanced green fluorescent protein (control) exhibited substantial PA- and LF-specific antibody responses at 4 weeks by both western blot (> 1:10,000 dilution) and enzyme-linked immunosorbent assay (ELISA) (mean end-point titer: 32,000-260,000), and contained anthrax LeTx-neutralizing activity in vitro, with peak titers approximating those of a rabbit hyperimmune antisera raised against soluble PA and LF. Compared to the monovalent groups (rAAV1/PA or rAAV1/LF), the bivalent group (rAAV1/PA + rAAV1/LF) exhibited marginally higher ELISA and neutralization activity with dual specificity for both PA and LF. The finding of robust neutralizing antibody responses after a single injection of these rAAV1-based vectors supports their further development as candidate anthrax vaccines.
Mol Ther 2009 Feb
PMID:Genetic vaccines for anthrax based on recombinant adeno-associated virus vectors. 1900 62

Bacillus anthracis, the causative agent of anthrax, is a dangerous biological weapon, as spores derived from drug-resistant strains cause infections for which antibiotic therapy is no longer effective. We sought to develop an anti-infective therapy for anthrax and targeted CapD, an enzyme that cleaves poly-gamma-D-glutamate capsule and generates amide bonds with peptidoglycan cross-bridges to deposit capsular material into the envelope of B. anthracis. In agreement with the model that capsule confers protection from phagocytic clearance, B. anthracis capD variants failed to deposit capsule into the envelope and displayed defects in anthrax pathogenesis. By screening chemical libraries, we identified the CapD inhibitor capsidin, 4-[(4-bromophenyl)thio]-3-(diacetylamino)benzoic acid), which covalently modifies the active-site threonine of the transpeptidase. Capsidin treatment blocked capsular assembly by B. anthracis and enabled phagocytic killing of non-encapsulated vegetative forms.
Mol Microbiol 2009 Jan
PMID:Capsule anchoring in Bacillus anthracis occurs by a transpeptidation reaction that is inhibited by capsidin. 1901 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>