Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Dengue is a serious public health problem in tropical and subtropical countries. It is caused by any of the four serologically distinct dengue viruses, namely DENV1-4. The viruses are transmitted by Aedes mosquitoes. Understanding various defence mechanisms of insects has become a prime area of research worldwide. In insects, the first line of defence against invading pathogens includes cellular mechanisms and a battery of antimicrobial peptides such as defensins, cecropins etc. Defensins--cationic, cysteine-rich peptides consisting of approximately 40 amino acids with broad-spectrum activity against Gram-positive bacteria--have been reported from a wide range of organisms. In the dengue vector mosquito, Aedes aegypti, three isoforms of defensins are reported to be expressed in a spatial and temporal fashion. This report presents the three-dimensional structures of the three isoforms of Ae. aegypti defensins predicted by comparative modeling. Prediction was done with Modeller 9v1 and the structures validated through a series of tests. The best results of the prediction study are presented, and may help lead to the discovery of new synthetic peptides or derivatives of defensins that could be useful in the control of vector-borne diseases.
J Mol Model 2009 May
PMID:In-silico homology modeling of three isoforms of insect defensins from the dengue vector mosquito, Aedes aegypti (Linn., 1762). 1908 24

The flavivirus 2'-O-nucleoside N-terminal RNA methyltransferase (MTase) enzyme is responsible for methylating the viral RNA cap structure. To increase our understanding of the mechanism of viral RNA cap binding we performed a detailed structural and biochemical characterization of the guanosine cap-binding pocket of the dengue (DEN) and yellow fever (YF) virus MTase enzymes. We solved an improved 2.1 A resolution crystal structure of DEN2 Mtase, new 1.5 A resolution crystal structures of the YF virus MTase domain in apo form, and a new 1.45 A structure in complex with guanosine triphosphate and RNA cap analog. Our structures clarify the previously reported DEN MTase structure, suggest novel protein-cap interactions, and provide a detailed view of guanine specificity. Furthermore, the structures of the DEN and YF proteins are essentially identical, indicating a large degree of structural conservation amongst the flavivirus MTases. Guanosine triphosphate analog competition assays and mutagenesis analysis, performed to analyze the biochemical characteristics of cap binding, determined that the major interaction points are (i) guanine ring via pi-pi stacking with Phe24, N1 hydrogen interaction with the Leu19 backbone carbonyl via a water bridge, and C2 amine interaction with Leu16 and Leu19 backbone carbonyls; (ii) ribose 2' hydroxyl interaction with Lys13 and Asn17; and (iii) alpha-phosphate interactions with Lys28 and Ser215. Based on our mutational and analog studies, the guanine ring and alpha-phosphate interactions provide most of the energy for cap binding, while the combination of the water bridge between the guanine N1 and Leu19 carbonyl and the hydrogen bonds between the C2 amine and Leu16/Leu19 carbonyl groups provide for specific guanine recognition. A detailed model of how the flavivirus MTase protein binds RNA cap structures is presented.
J Mol Biol 2009 Feb 06
PMID:Analysis of flavivirus NS5 methyltransferase cap binding. 1910 64

Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational changes in the E protein and is an essential step in the virus life cycle. In this study, we analyzed the pre-fusion and post-fusion structures of the dengue virus E protein to identify potential novel sites that could bind small molecules, which could interfere with the conformational transitions that mediate the fusion process. We used an in silico virtual screening approach combining three different docking algorithms (DOCK, GOLD and FlexX) to identify compounds that are likely to bind to these sites. Seven structurally diverse molecules were selected to test experimentally for inhibition of dengue virus propagation. The best compound showed an IC(50) in the micromolar range against dengue virus type 2.
J Comput Aided Mol Des 2009 Jun
PMID:Identification of novel target sites and an inhibitor of the dengue virus E protein. 1924 Nov 20

Dengue is a very rapidly growing public health problem being currently faced by approximately 40% of the global population living in more than a hundred tropical and sub-tropical countries. It is a viral disease, caused by four types of dengue viruses, transmitted by mosquitoes, to an estimated 50 million people each year. Vector control methods to contain transmission have not been successful and there is currently no useful diagnostic test, drug or vaccine to combat dengue disease. However, as a result of the heightened awareness of its magnitude and its potential to spread beyond the tropical world, dengue has begun to emerge out of the list of neglected diseases in recent years. New interest in this disease has drawn scientists from multiple disciplines into the dengue arena. This has resulted in novel insights into several aspects of dengue virus biology and identified potential drug targets. Several tetravalent vaccines are being developed. Newer animal models that mirror some of the salient features of dengue disease are becoming available to investigate the mechanism of pathogenesis and to aid in drug and vaccine discovery efforts. The realization that therapeutic and prophylactic intervention can be cost-effective has resulted in vigorous industry-driven translational initiatives to develop drugs and vaccines. Dengue research is at a critical juncture and the implementation of existing knowledge supplemented by a better understanding of pathogenesis promises to make a tangible impact in the combat against dengue in the coming years.
Curr Mol Med 2009 Mar
PMID:Dengue: recent advances in biology and current status of translational research. 1927 24

Dengue virus belongs to the family Flaviviridae and is a major emerging pathogen for which the development of vaccines and antiviral therapy has seen little success. The NS3 viral protease is a potential target for antiviral drugs since it is required for virus replication. The goal of this study was to identify novel dengue virus (type 2; DEN2V) protease inhibitors for eventual development as effective anti-flaviviral drugs. The EUDOC docking program was used to computationally screen a small-molecule library for compounds that dock into the P1 pocket and the catalytic site of the DEN2V NS3 protease domain apo-structure [Murthy, K., Clum, S., Padmanabhan, R., 1999. Crystal structure and insights into interaction of the active site with substrates by molecular modeling and structural analysis of mutational effects. J. Biol. Chem. 274, 5573-5580] and the Bowman-Birk inhibitor-bound structure [Murthy, K., Judge, K., DeLucas, L., Padmanabhan, R., 2000. Crystal structure of dengue virus NS3 protease in complex with a Bowman-Birk inhibitor: implications for flaviviral polyprotein processing and drug design. J. Mol. Biol. 301, 759-767]. The top 20 computer-identified hits that demonstrated the most favorable scoring "energies" were selected for in vitro assessment of protease inhibition. Preliminary protease activity assays demonstrated that more than half of the tested compounds were soluble and exhibited in vitro inhibition of the DEN2V protease. Two of these compounds also inhibited viral replication in cell culture experiments, and thus are promising compounds for further development.
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PMID:Structure-based discovery of dengue virus protease inhibitors. 1942 1

Dengue virus (DV) infection depends on a step of membrane fusion, which occurs in the acidic environment of the endosome. This process is mediated by virus surface envelope glycoprotein, in which the loop between residues D98-G112 is considered to be crucial, acting as a fusion peptide. Here, we have characterized functionally and structurally the interaction between the DV fusion peptide and different model membranes by fluorescence and NMR. Its interaction was strongest in dodecylphosphocholine (DPC) micelles and anionic phosphatidylcholine/phosphatidylglycerol vesicles, the only vesicle that was fused by DV fusion peptide. The three-dimensional structure of DV fusion peptide bound to DPC micelles was solved by solution homonuclear NMR with an r.m.s.d. of 0.98 A. The most striking result obtained from the solution structure was the hydrophobic triad formed by residues W101, L107, and F108, pointing toward the same direction, keeping the segment between G102 and G106 in a loop conformation. The interaction of DV fusion peptide with phosphatidylcholine/phosphatidylglycerol vesicles was also mapped by transfer-nuclear Overhauser enhancement (NOE) experiments, in which the majority of the NOE cross-peaks were from the hydrophobic triad, corroborating the DPC-bound structure. Substitution of the residue W101 by an alanine residue completely abolished membrane binding and, thus, fusion by the peptide and its NOE cross-peaks. In conclusion, the 15-residue DV fusion peptide has intrinsic ability to promote membrane fusion, most likely due to the hydrophobic interaction among the residues W101, L107, and F108, which maintains its loop in the correct spatial conformation.
J Mol Biol 2009 Sep 25
PMID:Interaction of the Dengue virus fusion peptide with membranes assessed by NMR: The essential role of the envelope protein Trp101 for membrane fusion. 1961 60

The pathogenic West Nile virus (WNV) and Dengue virus (DV) are growing global threats for which there are no specific treatments. Both viruses possess a two component NS2B/NS3 protease which cleaves viral precursor proteins. Whereas for the WNV protease two crystal structures in complex with an inhibitor have been solved recently, no such information is available for the DV protease. Here, we report the generation of a homology model of DV NS2B/NS3 protease. Since it is known from the related WNV protease that it adopts a distinct conformation in free and in inhibitor-complexed form, a special emphasis was given to the analysis of the protease flexibility. Therefore, several models of DV NS2B/NS3 protease complexed with the peptidic inhibitor (Bz-Nle(P4)-Lys(P3)-Arg(P2)-Arg(P1)-H) were generated. The first DV protease model (DV-1) was constructed using the available crystal structure of the apo DV NS2B/NS3 protease. The second model (DV-2) was built taking the WNV NS3/NS2B protease in the inhibitor-complexed form as the template structure. Molecular dynamics simulations which were carried out for the WNV crystal structures as well as for the DV models provided an understanding of the role of NS2B for maintaining the protease in the active conformation. It was also demonstrated that NS2B is not only important for maintaining NS3 in the active form, but is also essential for establishing the interaction between residues from the S2 pocket and the peptidic inhibitor. The DV NS2B/NS3 model in the productive conformation can now be used for structure-based design purposes.
J Mol Recognit
PMID:Homology modeling and molecular dynamics simulations of Dengue virus NS2B/NS3 protease: insight into molecular interaction. 1969 93

Horizontal gene transfer and recombination play a major role in microbial evolution and have been detected in diverse groups, including many of medical relevance such as HIV and dengue virus. In the absence of mechanistic barriers, the evolutionary success of a particular recombination event is determined by whether the recombinant genotype suffers a fitness cost through the disruption of favorable epistatic interactions within the genome, and if so, the extent to which this fitness cost might be mitigated by subsequent compensatory evolution. To investigate the importance of epistatic interactions between genes and the evolutionary viability of a homologous recombination event between diverged ancestral genotypes, we constructed two recombinant microvirid bacteriophages by exchanging their alleles of the gene encoding the coat protein. The coding sequences for this gene differ by approximately 8% at the amino acid level and were interchanged between two ancestral phages related to varphiX174 and well adapted to their culture conditions. Because the recombinant phages showed drastically reduced fitnesses, we further explored their evolutionary viability by subjecting replicate lines of each of them to selection. We found that all four lineages achieved fitnesses commensurate with ancestral fitnesses in as few as 60 generations, and on average, the first substitution accounted for more than half of the total fitness recovery. Fitness recovery required three to five substitutions in each lineage, and overall eight of the nine essential phage genes were involved, suggesting extensive epistatic interactions throughout the genome. Interestingly, the proteins with the most extensive and apparent physical interactions with the exchanged protein in the viral capsid did not appear to have much of a role in fitness recovery. This result appears to be a consequence of the conservation of the amino acid residues involved in the interactions. It suggests that strong epistatic interactions are less important than weaker, transient ones in producing genic incompatibilities because they preclude variability in the interacting regions of the proteins.
Mol Biol Evol 2009 Dec
PMID:Genic incompatibilities in two hybrid bacteriophages. 1972 36

Aedes albopictus, a mosquito originally from Southeast Asia, is considered to be one of the main vectors of dengue fever, yellow fever and other arboviruses. We examined the genetic variability and population structure of 68 individuals of Ae. albopictus collected from five neighborhoods of the city of Manaus, based on the mitochondrial gene coding for NADH dehydrogenase subunit 5 (ND5). Two haplotypes were found, separated by a single mutational event (T <--> C), with extremely low levels of genetic variability (h = 0.187 +/- 0.059; pi = 0.00044 +/- 0.00014). Based on AMOVA, we concluded that most of the variation (99.08%) occurred within populations, though the levels of variation were not significant. Neutrality tests (Tajima's D and Fu's Fs) were non-significant, indicating that these populations are in genetic equilibrium. The most frequent haplotype (H1) is restricted to Brazilian populations of Ae. albopictus, while the rarer haplotype (H2) is shared with populations from the United States and Asia. We suggest that the reduced variability and low genetic structure identified in our study is a consequence of the recent introduction of this species in Manaus, possibly through a founder effect, followed by expansion throughout the city neighborhoods. Genetic similarity would therefore be due to insufficient time to have accumulated genetic differences between the populations of Ae. albopictus and not to extensive gene flow among them.
Genet Mol Res 2009 Aug 18
PMID:Reduced levels of genetic variation in Aedes albopictus (Diptera: Culicidae) from Manaus, Amazonas State, Brazil, based on analysis of the mitochondrial DNA ND5 gene. 1973 Dec 20

Aedes aegypti is a major vector of arthropod-borne viruses such as yellow fever virus and dengue viruses. Efforts to discern the function of genes involved in important behaviours, such as vector competence and host seeking through reverse genetics, would greatly benefit from the ability to generate targeted gene disruptions. Homing endonucleases are selfish elements which catalyze double-stranded DNA (dsDNA) breaks in a sequence-specific manner. In this report we demonstrate that the homing endonucleases I-PpoI, I-SceI, I-CreI and I-AniI are all able to induce dsDNA breaks in adult female Ae. aegypti chromosomes as well as catalyze the somatic excision of a transgene. These experiments provide evidence that homing endonucleases can be used to manipulate the genome of this important disease vector.
Insect Mol Biol 2009 Oct
PMID:Homing endonucleases catalyze double-stranded DNA breaks and somatic transgene excision in Aedes aegypti. 1975 40


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