NS2B/NS3 protease: allosteric effect of mutations associated with the pathogenicity of tick-borne encephalitis virus

• Published in: Journal of biomolecular structure & dynamics Vol. 30; no. 6; pp. 638 - 651
• Main Authors: Potapova, Ulyana V., Feranchuk, Sergey I., Potapov, Vladimir V., Kulakova, Nina V., Kondratov, Ilya G., Leonova, Galina N., Belikov, Sergey I.
• Format: Journal Article
• Language: English
• Published: England Routledge 01.01.2012
• Subjects: Allosteric properties; Allosteric Regulation; Amino Acid Motifs; Amino Acid Sequence; Amino Acid Substitution; Catalytic Domain; conformational analysis; Crystal structure; Encephalitis Viruses, Tick-Borne - enzymology; Encephalitis Viruses, Tick-Borne - pathogenicity; Enzymes; flaviviral protease; Homology; Hydrophobic and Hydrophilic Interactions; molecular dynamic; Molecular Dynamics Simulation; Molecular modelling; Molecular Sequence Data; Mutation; NS3 protein; Pathogenicity; Protein Interaction Domains and Motifs; Proteinase; Sequence Analysis, Protein; Sequence Homology, Amino Acid; Serine Proteases - chemistry; Serine Proteases - genetics; Structural Homology, Protein; Tick-borne encephalitis; Tick-borne encephalitis virus; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Virulence; West Nile virus
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2012.689697

The sequences of the protease domain of the tick-borne encephalitis (TBE) virus NS3 protein have two amino acid substitutions, 16 R→K and 45 S→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; 20 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.