ArticleJournal of molecular graphics & modelling2010
Structural basis for substrate specificity of alphavirus nsP2 proteases.
Article in Journal of molecular graphics & modelling, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Novel computational pipeline to identify target sites for broad spectrum antiviral drugs.Antiviral research · 2026Article
- Alphavirus nsP2: A Multifunctional Regulator of Viral Replication and Promising Target for Anti-Alphavirus Therapies.Reviews in medical virology · 2025Review
- Review
- Withaferin A inhibits Chikungunya virus nsP2 protease and shows antiviral activity in the cell culture and mouse model of virus infection.PLoS pathogens · 2024Article
- Identification of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Self-inhibited State of Venezuelan Equine Encephalitis Virus (VEEV) nsP2 Cysteine Protease: A Crystallographic and Molecular Dynamics Analysis.Journal of molecular biology · 2023Article
- Structural insights into the inhibition of the nsP2 protease from Chikungunya virus by molecular modeling approaches.Journal of molecular modeling · 2022Article
- Article
- Specificity Studies of the Venezuelan Equine Encephalitis Virus Non-Structural Protein 2 Protease Using Recombinant Fluorescent Substrates.International journal of molecular sciences · 2020Article
- Computer-Aided Design, Synthesis, and Antiviral Evaluation of Novel Acrylamides as Potential Inhibitors of E3-E2-E1 Glycoproteins Complex from Chikungunya Virus.Pharmaceuticals (Basel, Switzerland) · 2020Article
- Timeliness of Proteolytic Events Is Prerequisite for Efficient Functioning of the Alphaviral Replicase.Journal of virology · 2018Article
- The medicinal chemistry of Chikungunya virus.Bioorganic & medicinal chemistry · 2017Review
- Chikungunya virus infectivity, RNA replication and non-structural polyprotein processing depend on the nsP2 protease's active site cysteine residue.Scientific reports · 2016Article
- Kinetic, Mutational, and Structural Studies of the Venezuelan Equine Encephalitis Virus Nonstructural Protein 2 Cysteine Protease.Biochemistry · 2016Article
- Chikungunya nsP2 protease is not a papain-like cysteine protease and the catalytic dyad cysteine is interchangeable with a proximal serine.Scientific reports · 2015Article
- Viral Polymerase-Helicase Complexes Regulate Replication Fidelity To Overcome Intracellular Nucleotide Depletion.Journal of virology · 2015Article
- Differences in Processing Determinants of Nonstructural Polyprotein and in the Sequence of Nonstructural Protein 3 Affect Neurovirulence of Semliki Forest Virus.Journal of virology · 2015Article
- Full length and protease domain activity of chikungunya virus nsP2 differ from other alphavirus nsP2 proteases in recognition of small peptide substrates.Bioscience reports · 2015Article
- Functional cross-talk between distant domains of chikungunya virus non-structural protein 2 is decisive for its RNA-modulating activity.The Journal of biological chemistry · 2014Article
- Presentation overrides specificity: probing the plasticity of alphaviral proteolytic activity through mutational analysis.Journal of virology · 2013Article
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Authors and funding
4 authors.
Funding
Abstract
The alphavirus nsP2 protease is essential for correct processing of the alphavirus nonstructural polyprotein (nsP1234) and replication of the viral genome. We have combined molecular dynamics simulations with our structural studies to reveal features of the nsP2 protease catalytic site and S1'-S4 subsites that regulate the specificity of the protease. The catalytic mechanism of the nsP2 protease appears similar to the papain-like cysteine proteases, with the conserved catalytic dyad forming a thiolate-imidazolium ion pair in the nsP2-activated state. Substrate binding likely stabilizes this ion pair. Analysis of bimolecular complexes of Venezuelan equine encephalitis virus (VEEV) nsP2 protease with each of the nsP1234 cleavage sites identified protease residues His(510), Ser(511), His(546) and Lys(706) as critical for cleavage site recognition. Homology modelling and molecular dynamics simulations of diverse alphaviruses and their cognate cleavage site sequences revealed general features of substrate recognition that operate across alphavirus strains as well as strain specific covariance between binding site and cleavage site residues. For instance, compensatory changes occurred in the P3 and S3 subsite residues to maintain energetically favourable complementary binding surfaces. These results help explain how alphavirus nsP2 proteases recognize different cleavage sites within the nonstructural polyprotein and discriminate between closely related cleavage targets.
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