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

The complement control protein (CCP) module (also known as SCR, CCP or sushi domain) is prevalent amongst proteins that regulate complement activation. Functional and mutagenesis studies have shown that in most cases two or more neighbouring CCP modules form specific binding sites for other molecules. Hence the orientation in space of a CCP module with respect to its neighbours and the flexibility of the intermodular junction are likely to be critical for function. Vaccinia virus complement control protein (VCP) is a complement regulatory protein composed of four tandemly arranged CCP modules. The solution structure of the carboxy-terminal half of this protein (CCP modules 3 and 4) has been solved previously. The structure of the central portion (modules 2 and 3, VCP approximately 2,3) has now also been solved using NMR spectroscopy at 37 degrees C. In addition, the backbone dynamics of VCP approximately 2,3 have been characterised by analysis of its (15)N relaxation parameters. Module 2 has a typical CCP module structure while module 3 in the context of VCP approximately 2,3 has some modest but significant differences in structure and dynamics to module 3 within the 3,4 pair. Modules 2 and 3 do not share an extensive interface, unlike modules 3 and 4. Only two possible NOEs were identified between the bodies of the modules, but a total of 40 NOEs between the short intermodular linker of VCP approximately 2,3 and the bodies of the two modules determines a preferred, elongated, orientation of the two modules in the calculated structures. The anisotropy of rotational diffusion has been characterised from (15)N relaxation data, and this indicates that the time-averaged structure is more compact than suggested by (1)H-(1)H NOEs. The data are consistent with the presence of many intermodular orientations, some of which are kinked, undergoing interconversion on a 10(-8)-10(-6) second time-scale. A reconstructed representation of modules 2-4 allows visualisation of the spatial arrangement of the 11 substitutions that occur in the more potent complement inhibitor from Variola (small pox) virus.
J Mol Biol 2001 Mar 16
PMID:Solution structure and dynamics of the central CCP module pair of a poxvirus complement control protein. 1124 23

Vaccination has eradicated smallpox and greatly decreased mortality and morbidity associated with a variety of viral and bacterial infectious diseases. However, conventional methodologies have failed to provide vaccines against many widespread deadly human diseases, among them HIV, malaria and cancer. Recombinant DNA vaccines have shown great promise in animal models in inducing protective immunity. In this review we will discuss their potential safe use in humans following recent advances in their use in animals, including non-human primates.
Curr Opin Mol Ther 2000 Aug
PMID:The evolution of DNA vaccines. 1124 75

A number of molecular forms of DNA polymerases have been reported to be involved in eukaryotic nuclear DNA replication, with contributions from alpha-, delta-, and epsilon-polymerases. It has been reported that delta-polymerase possessed a central role in DNA replication in archaea, whose ancestry are thought to be closely related to the ancestor of eukaryotes. Indeed, in vitro experiment shown here suggests that delta-polymerase has the potential ability to start DNA synthesis immediately after RNA primer synthesis. Therefore, the question arises, where did the alpha-polymerase come from? Phylogenetic analysis based on the nucleotide sequence of several conserved regions reveals that two poxviruses, vaccinia and variola viruses, have polymerases similar to eukaryotic alpha-polymerase rather than delta-polymerase, while adenovirus, herpes family viruses, and archaeotes have eukaryotic delta-like polymerases, suggesting that the eukaryotic alpha-polymerase gene is derived from a poxvirus-like organism, which had some eukaryote-like characteristics. Furthermore, the poxvirus's proliferation independent from the host-cell nucleus suggests the possibility that this virus could infect non-nucleated cells, such as ancestral eukaryotes. I wish to propose here a new hypothesis for the origin of the eukaryotic nucleus, posing symbiotic contact of an orthopoxvirus ancestor with an archaebacterium, whose genome already had a delta-like polymerase gene.
J Mol Evol 2001 May
PMID:Poxviruses and the origin of the eukaryotic nucleus. 1144 45

The occurrence of infectious disease represents a failure of the immune system, a failure that must be prevented by effective vaccination or remedied by treatment. Vaccination against acute diseases such as smallpox and polio are very effective, due to the rapid and increased immune response of vaccinated individuals upon natural infection. In contrast, effective vaccination against intracellular pathogens that cause chronic diseases, such as the leishmaniases, tuberculosis and AIDS, has not been achieved. Clinical observations suggest cell-mediated, Th1 responses, exclusive of antibody production and the generation of Th2 cells, are optimally protective against these intracellular pathogens. Effective vaccination must ensure the generation of such a protective response. We explore here whether understanding very broad features of the regulation of the immune response can accommodate modern findings on the immunological features of these diseases, and provide a perspective within which strategies for effective vaccination and treatment can be developed.
Cell Mol Life Sci 2001 Nov
PMID:Vaccination against and treatment of tuberculosis, the leishmaniases and AIDS: perspectives from basic immunology and immunity to chronic intracellular infections. 1176 85

The use of microorganisms as agents of biological warfare is considered inevitable for several reasons, including ease of production and dispersion, delayed onset, ability to cause high rates of morbidity and mortality, and difficulty in diagnosis. Biological agents that have been identified as posing the greatest threat are variola major (smallpox), Bacillus anthracis (anthrax), Yersinia pestis (plague), Clostridium botulinum toxin (botulism), Francisella tularensis (tularaemia), filoviruses (Ebola hemorrrhagic fever and Marburg hemorrhagic fever), and arenaviruses Lassa (Lassa fever) and Junin (Argentine hemorrhagic fever). The pathogenesis, clinical manifestations, diagnosis, and treatment of these agents are discussed. Rapid identification and diagnosis using molecular diagnostic techniques such as PCR is an essential element in the establishment of coordinated laboratory response systems and is the focus of current research and development. Molecular techniques for detection and identification of these organisms are reviewed.
Mol Diagn 2001 Dec
PMID:Biological agents: weapons of warfare and bioterrorism. 1177 97

Genes and proteins of the kelch superfamily were structurally analyzed in the smallpox (SPV), monkeypox (MPV), cowpox (CPV), and vaccinia (VV) viruses. Genes potentially coding for the kelch-like proteins were found only in the variable terminal regions of the orthopoxvirus genome. The set and sizes of their protein products varied with species. All genes of the superfamily proved to be disrupted by mutations in SPV, which is highly pathogenic for its only host, man. The largest set of kelch-like proteins was observed for CPV, which is low-pathogenic for humans and has the broadest animal host range. The kelch-like proteins of one virus showed low homology to each other, whereas isologs of different viruses were highly homologous. The results testified to the earlier assumption that CPV is the most ancient and an ancestor of the other orthopoxviruses pathogenic for humans.
Mol Biol (Mosk)
PMID:[Orthopoxvirus genes for Kelch-like proteins. I. Analysis of species specific differences by gene structure and organization]. 1217 63

Recently, there has been renewed interest in finding orally active drugs against smallpox. Cidofovir (CDV) given by parenteral injection has been shown to protect against lethal poxvirus infection. We have been interested in the synthesis and evaluation of orally active derivatives of CDV. Previous studies showed that the CDV and cyclic cidofovir (cCDV) analogs 1-O-hexa-decyloxypropyl-CDV (HDP-CDV) and 1-O-hexadecyloxypropyl-cCDV (HDP-cCDV), show >100-fold increases in antiviral activity versus the unmodified nucleosides against cells infected with orthopoxviruses, cowpox, and vaccinia virus. In contrast to CDV, HDP-CDV is orally bioavailable and has been reported to be orally active in lethal cowpox virus infection in mice. To assess the metabolic basis for the increased antiviral activity of HDP-CDV in vitro, we studied the cellular uptake and anabolic metabolism of (14)C-labeled CDV, cCDV, and their alkoxyalkanol esters HDP-CDV and HDP-cCDV. HDP-CDV and HDP-cCDV were taken up rapidly by MRC-5 human lung fibroblasts in vitro, but uptake of CDV and cCDV was much slower. Analysis of cellular metabolites showed that levels of cidofovir diphosphate (CDV-DP), the active antiviral compound, were >100 times greater with HDP-CDV than levels observed with CDV. When cells were exposed to HDP-CDV, the intracellular half-life of CDV-DP was 10 days versus 2.7 days reported when cells are exposed to CDV. HDP-CDV seems to circumvent poor cellular uptake by rapid association with cellular membrane phospholipids, whereas CDV uptake proceeds via the slow process of fluid endocytosis.
Mol Pharmacol 2003 Mar
PMID:Increased antiviral activity of 1-O-hexadecyloxypropyl-[2-(14)C]cidofovir in MRC-5 human lung fibroblasts is explained by unique cellular uptake and metabolism. 1260 77

The review considers recent data on the structural-functional organization of the genome of orthopoxviruses pathogenic for humans, including the variola, monkeypox, cowpox, and vaccinia viruses. Emphasis was placed on the structure of molecular virulence factors that suppress the inflammatory reactions, immune response, and interferon effects induced by virus infection.
Mol Biol (Mosk)
PMID:[Immunomodulatory proteins of orthopoxviruses]. 1262 44

A method for one-stage rapid identification of the four orthopovirus species, which are pathogenic to humans, involving multiplex polymerase chain reaction (MPCR) was developed. Five pairs of oligonucleotides primers were simultaneously used in the mentioned MPCR assay of orthopoxvirus DNA; one of the pairs was genus-specific, the remaining four primers were species-specific for variola, monkey-pox, cowpox and vaccine-pox. The specificity and sensitivity of the developed method were evaluated through analyzing the DNA samples of 55 orthopoxvirus strains, including samples isolated from human clinical materials.
Mol Gen Mikrobiol Virusol 2003
PMID:[Multiplex PCR analysis for species specific express-identification of orthopoxviruses]. 1265 47

The potential for a bioterrorism-induced smallpox outbreak has been much discussed of late. The literature of the late 1960s stressed that the distinction between smallpox and the other viral-induced vesicle-forming diseases, namely varicella zoster and disseminated herpes simplex, was difficult to make. Given that the cutaneous manifestations of smallpox would be among the initial symptoms, we reviewed 2 cases of smallpox diagnosed in South America in the 1970s in conjunction with 9 cases of multiple skin vesicles diagnosed as either disseminated herpes simplex or varicella-zoster. These were examined by routine hematoxylin and eosin stain (H&E) as well as by in situ hybridization. A blind review of the cases demonstrated that each showed striking intraepithelial vesicles containing multinucleated squamous cells exhibiting a ground glass appearance of the nuclear chromatin. Thus, as expected, routine H&E examination could not differentiate the 2 smallpox cases from the other 9 samples. In situ hybridization easily distinguished the 2 cases of smallpox from the other 9 samples, 5 of which contained varicella-zoster (two had been misdiagnosed as herpes) and the other 4 were disseminated herpes simplex. The in situ test, readily accomplished in any histology-based molecular laboratory in 4 hours, allows for the rapid and specific identification of smallpox infection and, importantly, its distinction from its mimics. Formalin fixation, which is optimal for in situ hybridization, guarantees the inactivation of the smallpox virus.
Diagn Mol Pathol 2003 Jun
PMID:Rapid diagnosis of smallpox infection and differentiation from its mimics. 1276 15


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