Homology modeling and molecular dynamics study of West Nile virus NS3 protease: A molecular basis for the catalytic activity increased by the NS2B cofactor

Zhou, Hong; Singh, N. Jiten; Kim, Kwang S.

doi:10.1002/prot.21129

Cited by 21 publications

(15 citation statements)

References 43 publications

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“…Finally, the whole system was slowly heated from 0 to 300 K over 100 ps before MD simulation. Trajectories were recorded every 1 ps during the entire MD simulation process [28]. A modeling averaged conformation was derived from the trajectories of the converged 32810–33600 ps.…”

Section: Methodsmentioning

confidence: 99%

Structural and Functional Analyses of a Sterol Carrier Protein in Spodoptera litura

Zhang

et al. 2014

PLoS ONE

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BackgroundsIn insects, cholesterol is one of the membrane components in cells and a precursor of ecdysteroid biosynthesis. Because insects lack two key enzymes, squalene synthase and lanosterol synthase, in the cholesterol biosynthesis pathway, they cannot autonomously synthesize cholesterol de novo from simple compounds and therefore have to obtain sterols from their diet. Sterol carrier protein (SCP) is a cholesterol-binding protein responsible for cholesterol absorption and transport.ResultsIn this study, a model of the three-dimensional structure of SlSCPx-2 in Spodoptera litura, a destructive polyphagous agricultural pest insect in tropical and subtropical areas, was constructed. Docking of sterol and fatty acid ligands to SlSCPx-2 and ANS fluorescent replacement assay showed that SlSCPx-2 was able to bind with relatively high affinities to cholesterol, stearic acid, linoleic acid, stigmasterol, oleic acid, palmitic acid and arachidonate, implying that SlSCPx may play an important role in absorption and transport of these cholesterol and fatty acids from host plants. Site-directed mutation assay of SlSCPx-2 suggests that amino acid residues F53, W66, F89, F110, I115, T128 and Q131 are critical for the ligand-binding activity of the SlSCPx-2 protein. Virtual ligand screening resulted in identification of several lead compounds which are potential inhibitors of SlSCPx-2. Bioassay for inhibitory effect of five selected compounds showed that AH-487/41731687, AG-664/14117324, AG-205/36813059 and AG-205/07775053 inhibited the growth of S. litura larvae.ConclusionsCompounds AH-487/41731687, AG-664/14117324, AG-205/36813059 and AG-205/07775053 selected based on structural modeling showed binding affinity to SlSCPx-2 protein and inhibitory effect on the growth of S. litura larvae.

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Section: Methodsmentioning

confidence: 99%

Structural and Functional Analyses of a Sterol Carrier Protein in Spodoptera litura

Zhang

et al. 2014

PLoS ONE

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“…NS3 serine protease of west Nile virus (WNV) plays important role in the assembly of infective virion, an attractive target for anti-WNV drug development. A series of models such as NS3, NS2B and NS2B have been generated using homology modeling (Zhou et al, 2006). The crystal structure coordinates of the hepatitis C virus NS3 protease has been used to generate homology model of the dengue 2 virus NS3 protease (Brinkworth et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Structural Modeling of the NS 3 helicase of Tick-borne encephalitis virus and their virtual screening of potent drugs using molecular docking

Singh

Somvanshi²

2009

Interdiscip Sci Comput Life Sci

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Homology modeling of NS3 helicase in Tick-borne encephalitis virus using known protein crystal structure was done. Its 3-D structure was evaluated and validated using PROCHECK comprising amino acid residues in favored region of Ramachandran plot. Helicase forms a large family of proteins which ubiquitously distributes in wide variety of organisms. It plays crucial role in transcription and replication of single-stranded viral RNA genomes. Consequently, NS3 represents an interesting target for the development of specific antiviral inhibitors. Several helicase inhibiting effective drugs and analogs were selected and the active amino acid residues were targeted. Levovirin, Ribamidine and Ribavirin were found more potent to inhibit TBEV on the basis of robust binding affinity between protein-drug interactions. This finding may help to understand the nature of helicase and development of specific anti-TBEV therapies.

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“…This polyprotein is cleaved into three structural (C, prM, and E) and seven nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins due to the combined and coordinated activities of host cell proteases in the ER and the viral protease complex (NS2B3) in the cytoplasm (27). The viral protease cleavages are mediated by the catalytic triad (His-51, Asp-75, and Ser-135) of the serine protease N-terminal domain of NS3 (56), with a hydrophilic segment of 40 residues from the transmembrane NS2B protein acting as a cofactor (55).…”

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confidence: 99%

Inhibition of the Type I Interferon Response in Human Dendritic Cells by Dengue Virus Infection Requires a Catalytically Active NS2B3 Complex

Rodríguez-Madoz

Belicha-Villanueva

Bernal-Rubio

et al. 2010

J Virol

127

123

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Dengue virus (DENV) is the most prevalent arthropod-borne human virus, able to infect and replicate in human dendritic cells (DCs), inducing their activation and the production of proinflammatory cytokines. However, DENV can successfully evade the immune response in order to produce disease in humans. Several mechanisms of immune evasion have been suggested for DENV, most of them involving interference with type I interferon (IFN) signaling. We recently reported that DENV infection of human DCs does not induce type I IFN production by those infected DCs, impairing their ability to prime naive T cells toward Th1 immunity. In this article, we report that DENV also reduces the ability of DCs to produce type I IFN in response to several inducers, such as infection with other viruses or exposure to Toll-like receptor (TLR) ligands, indicating that DENV antagonizes the type I IFN production pathway in human DCs. DENV-infected human DCs showed a reduced type I IFN response to Newcastle disease virus (NDV), Sendai virus (SeV), and Semliki Forest virus (SFV) infection and to the TLR3 agonist poly(I:C). This inhibitory effect is DENV dose dependent, requires DENV replication, and takes place in DENV-infected DCs as early as 2 h after infection. Expressing individual proteins of DENV in the presence of an IFN-␣/␤ production inducer reveals that a catalytically active viral protease complex is required to reduce type I IFN production significantly. These results provide a new mechanism by which DENV evades the immune system in humans.Dengue virus (DENV), a member of the Flaviviridae family and grouped within the Flavivirus genus (27), is the most prevalent arthropod-borne human virus with significant medical and biodefense importance (8,27). DENV is transmitted by mosquitoes, usually Aedes aegypti, with an estimated 100 million cases per year and 2.5 billion people at risk (53). Clinical manifestations include dengue fever, a febrile illness with rash, and dengue hemorrhagic fever, a severe and often lethal illness (53). There are four DENV serotypes (DENV1 to -4), and infection with one serotype confers life-long protection against that serotype at least by the induction of neutralizing antibodies (17). Currently there is no vaccine or effective antiviral treatment against this virus, and the most effective protective measures involve mosquito control.The DENV genome is a positive-strand RNA molecule of about 11 kb in length, with one single open reading frame (ORF) flanked by 5Ј and 3Ј nontranslated regions (27). After viral infection and the release of the viral nucleocapsid into the cytosol, a 3,391-amino-acid (aa)-long polyprotein is translated from the viral RNA at the surface of the endoplasmic reticulum (ER) (27). This polyprotein is cleaved into three structural (C, prM, and E) and seven nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins due to the combined and coordinated activities of host cell proteases in the ER and the viral protease complex (NS2B3) in the cytoplasm (27). The viral protease cle...

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Homology modeling and molecular dynamics study of West Nile virus NS3 protease: A molecular basis for the catalytic activity increased by the NS2B cofactor

Cited by 21 publications

References 43 publications

Structural and Functional Analyses of a Sterol Carrier Protein in Spodoptera litura

Structural and Functional Analyses of a Sterol Carrier Protein in Spodoptera litura

Structural Modeling of the NS 3 helicase of Tick-borne encephalitis virus and their virtual screening of potent drugs using molecular docking

Inhibition of the Type I Interferon Response in Human Dendritic Cells by Dengue Virus Infection Requires a Catalytically Active NS2B3 Complex

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