NS2B/NS3 protease: allosteric effect of mutations associated with the pathogenicity of tick-borne encephalitis virus.
Summary of "NS2B/NS3 protease: allosteric effect of mutations associated with the pathogenicity of tick-borne encephalitis virus."
The sequences of the protease domain of the tick-borne encephalitis (TBE) virus NS3 protein have two amino acid substitutions, 16 Râ†’K and 45 Sâ†’F, in the highly pathogenic and poorly pathogenic strains of the virus, respectively. Two models of the NS2B-NS3 protease complex for the highly pathogenic and poorly pathogenic strains of the virus were constructed by homology modeling using the crystal structure of West Nile virus NS2B-NS3 protease as a template; 20â€‰ns molecular dynamic simulations were performed for both models, the trajectories of the dynamic simulations were compared, and the averaged distance between the two models was calculated for each residue. Conformational differences between two models were revealed in the identified pocket. The different conformations of the pocket resulted in different orientations of the NS2B segment located near the catalytic triad. In the model of the highly pathogenic TBE virus the identified pocket had a more open conformation compared to the poorly pathogenic model. We propose that conformational changes in the active protease center, caused by two amino acid substitutions, can influence enzyme functioning and the virulence of the virus.
a Limnological Institute, Siberian Branch of the Russian Academy of Sciences , 3, Ulan-Batorskaya St. , Irkutsk , 664033 , Russian Federation.
This article was published in the following journal.
Name: Journal of biomolecular structure & dynamics
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22730949
- DOI: http://dx.doi.org/10.1080/07391102.2012.689697
Medical and Biotech [MESH] Definitions
Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene.
An effect usually, but not necessarily, beneficial that is attributable to an expectation that the regimen will have an effect, i.e., the effect is due to the power of suggestion.
The modification of the reactivity of ENZYMES by the binding of effectors to sites (ALLOSTERIC SITES) on the enzymes other than the substrate BINDING SITES.
Extracellular protease inhibitors that are secreted from FIBROBLASTS. They form a covalent complex with SERINE PROTEASES and can mediate their cellular internalization and degradation.
Hiv Protease Inhibitors
Inhibitors of HIV PROTEASE, an enzyme required for production of proteins needed for viral assembly.
Flaviviral NS3 serine proteases require the NS2B cofactor region (cNS2B) to be active. Recent crystal structures of West Nile virus (WNV) protease in complex with inhibitors revealed that cNS2B partic...
Dengue virus, belongs to Flaviviridae, is an arthropod transmitted virus that threatens millions of people's lives. As with other flaviviruses, a positive single-stranded 11-kilobases RNA in the dengu...
The underlying mechanisms driving the evolution of drug resistance in human immunodeficiency virus (HIV) are only partially understood. We investigated the evolutionary cost of the major resistance mu...
Sustained suppression of viral replication in HIV-1 infected patients is especially hampered by the emergence of HIV-1 drug resistance. The mechanisms of drug resistance mainly involve mutations direc...
An in silico fragment-based drug design approach was devised and applied towards the identification of small molecule inhibitors of the dengue virus (DENV) NS2B-NS3 protease. Currently, no DENV protea...
This study will assess the efficacy of subsequent protease inhibitor (PI)-containing therapy in subjects who have acquired HIV-1 protease mutations whilst receiving a GW433908 (fosamprenav...
The objective of this study is to demonstrate the safety and efficacy of tipranavir/ritonavir versus an active control arm in highly treatment experienced Human immunodeficiency virus-1 in...
Study of Protease Inhibitor Regimen Switch in HIV-1 Infected Patients With Undetectable Viral Load to Prove the Non-inferiority of Once Daily Dose Regimen Versus the Current Twice Daily Regimen to Maintain the Viral Load Under the Limit of Detection.
Darunavir boosted with ritonavir (darunavir/r) is a powerful protease inhibitor, able to reduce the viral load in patients infected with multi-resistant HIV strains; In vitro and in vivo s...
Tipranavir is a drug with a high antiretroviral activity, also in presence of major mutations in the protease gene. However, its necessity of being co-administered with 400 mg of ritonavir...
The purpose of the study is to study the effects of switching from an antiretroviral combination that includes two ritonavir boosted protease inhibitors to replacement of these two proteas...