2hwk Citations

The crystal structure of the Venezuelan equine encephalitis alphavirus nsP2 protease.

Structure 14 1449-58 (2006)
Cited: 55 times
EuropePMC logo PMID: 16962975


Alphavirus replication and propagation is dependent on the protease activity of the viral nsP2 protein, which cleaves the nsP1234 polyprotein replication complex into functional components. Thus, nsP2 is an attractive target for drug discovery efforts to combat highly pathogenic alphaviruses. Unfortunately, antiviral development has been hampered by a lack of structural information for the nsP2 protease. Here, we report the crystal structure of the nsP2 protease (nsP2pro) from Venezuelan equine encephalitis alphavirus determined at 2.45 A resolution. The protease structure consists of two distinct domains. The nsP2pro N-terminal domain contains the catalytic dyad cysteine and histidine residues organized in a protein fold that differs significantly from any known cysteine protease or protein folds. The nsP2pro C-terminal domain displays structural similarity to S-adenosyl-L-methionine-dependent RNA methyltransferases and provides essential elements that contribute to substrate recognition and may also regulate the structure of the substrate binding cleft.

Reviews - 2hwk mentioned but not cited (2)

Articles - 2hwk mentioned but not cited (8)

  1. Functional cross-talk between distant domains of chikungunya virus non-structural protein 2 is decisive for its RNA-modulating activity. Das PK, Merits A, Lulla A. J. Biol. Chem. 289 5635-5653 (2014)
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  6. Chikungunya nsP2 protease is not a papain-like cysteine protease and the catalytic dyad cysteine is interchangeable with a proximal serine. Saisawang C, Saitornuang S, Sillapee P, Ubol S, Smith DR, Ketterman AJ. Sci Rep 5 17125 (2015)
  7. Kinetic, Mutational, and Structural Studies of the Venezuelan Equine Encephalitis Virus Nonstructural Protein 2 Cysteine Protease. Hu X, Compton JR, Leary DH, Olson MA, Lee MS, Cheung J, Ye W, Ferrer M, Southall N, Jadhav A, Morazzani EM, Glass PJ, Marugan J, Legler PM. Biochemistry 55 3007-3019 (2016)
  8. Molecular Modeling and Docking Study to Elucidate Novel Chikungunya Virus nsP2 Protease Inhibitors. Agarwal T, Asthana S, Bissoyi A. Indian J Pharm Sci 77 453-460 (2015)

Reviews citing this publication (7)

  1. The Interplay of Viral and Host Factors in Chikungunya Virus Infection: Targets for Antiviral Strategies. Wong KZ, Chu JJH. Viruses 10 (2018)
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Articles citing this publication (38)

  1. Evasion of the innate immune response: the Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II. Akhrymuk I, Kulemzin SV, Frolova EI. J. Virol. 86 7180-7191 (2012)
  2. Mapping of Chikungunya virus interactions with host proteins identified nsP2 as a highly connected viral component. Bouraï M, Lucas-Hourani M, Gad HH, Drosten C, Jacob Y, Tafforeau L, Cassonnet P, Jones LM, Judith D, Couderc T, Lecuit M, André P, Kümmerer BM, Lotteau V, Desprès P, Tangy F, Vidalain PO. J. Virol. 86 3121-3134 (2012)
  3. Development of Sindbis viruses encoding nsP2/GFP chimeric proteins and their application for studying nsP2 functioning. Atasheva S, Gorchakov R, English R, Frolov I, Frolova E. J. Virol. 81 5046-5057 (2007)
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  6. Homology modeling, molecular dynamics, e-pharmacophore mapping and docking study of Chikungunya virus nsP2 protease. Singh KhD, Kirubakaran P, Nagarajan S, Sakkiah S, Muthusamy K, Velmurgan D, Jeyakanthan J. J Mol Model 18 39-51 (2012)
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  8. Random insertion mutagenesis of sindbis virus nonstructural protein 2 and selection of variants incapable of downregulating cellular transcription. Frolov I, Garmashova N, Atasheva S, Frolova EI. J. Virol. 83 9031-9044 (2009)
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  10. Role for conserved residues of sindbis virus nonstructural protein 2 methyltransferase-like domain in regulation of minus-strand synthesis and development of cytopathic infection. Mayuri, Geders TW, Smith JL, Kuhn RJ. J. Virol. 82 7284-7297 (2008)
  11. Computer-aided identification, design and synthesis of a novel series of compounds with selective antiviral activity against chikungunya virus. Bassetto M, De Burghgraeve T, Delang L, Massarotti A, Coluccia A, Zonta N, Gatti V, Colombano G, Sorba G, Silvestri R, Tron GC, Neyts J, Leyssen P, Brancale A. Antiviral Res. 98 12-18 (2013)
  12. Enzymatic defects of the nsP2 proteins of Semliki Forest virus temperature-sensitive mutants. Balistreri G, Caldentey J, Kääriäinen L, Ahola T. J. Virol. 81 2849-2860 (2007)
  13. Hypervariable domain of nonstructural protein nsP3 of Venezuelan equine encephalitis virus determines cell-specific mode of virus replication. Foy NJ, Akhrymuk M, Shustov AV, Frolova EI, Frolov I. J. Virol. 87 7569-7584 (2013)
  14. Viral Polymerase-Helicase Complexes Regulate Replication Fidelity To Overcome Intracellular Nucleotide Depletion. Stapleford KA, Rozen-Gagnon K, Das PK, Saul S, Poirier EZ, Blanc H, Vidalain PO, Merits A, Vignuzzi M. J. Virol. 89 11233-11244 (2015)
  15. High-resolution functional mapping of the venezuelan equine encephalitis virus genome by insertional mutagenesis and massively parallel sequencing. Beitzel BF, Bakken RR, Smith JM, Schmaljohn CS. PLoS Pathog. 6 e1001146 (2010)
  16. Molecular cloning, overproduction, purification and biochemical characterization of the p39 nsp2 protease domains encoded by three alphaviruses. Zhang D, Tözsér J, Waugh DS. Protein Expr. Purif. 64 89-97 (2009)
  17. A compact viral processing proteinase/ubiquitin hydrolase from the OTU family. Lombardi C, Ayach M, Beaurepaire L, Chenon M, Andreani J, Guerois R, Jupin I, Bressanelli S. PLoS Pathog. 9 e1003560 (2013)
  18. Chikungunya virus infectivity, RNA replication and non-structural polyprotein processing depend on the nsP2 protease's active site cysteine residue. Rausalu K, Utt A, Quirin T, Varghese FS, Žusinaite E, Das PK, Ahola T, Merits A. Sci Rep 6 37124 (2016)
  19. Molecular defects caused by temperature-sensitive mutations in Semliki Forest virus nsP1. Lulla V, Sawicki DL, Sawicki SG, Lulla A, Merits A, Ahola T. J. Virol. 82 9236-9244 (2008)
  20. Role for subgenomic mRNA in host translation inhibition during Sindbis virus infection of mammalian cells. Patel RK, Burnham AJ, Gebhart NN, Sokoloski KJ, Hardy RW. Virology 441 171-181 (2013)
  21. Nuclear import and export of Venezuelan equine encephalitis virus nonstructural protein 2. Montgomery SA, Johnston RE. J. Virol. 81 10268-10279 (2007)
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  23. Discovery of a novel compound with anti-venezuelan equine encephalitis virus activity that targets the nonstructural protein 2. Chung DH, Jonsson CB, Tower NA, Chu YK, Sahin E, Golden JE, Noah JW, Schroeder CE, Sotsky JB, Sosa MI, Cramer DE, McKellip SN, Rasmussen L, White EL, Schmaljohn CS, Julander JG, Smith JM, Filone CM, Connor JH, Sakurai Y, Davey RA. PLoS Pathog. 10 e1004213 (2014)
  24. Alphavirus protease inhibitors from natural sources: A homology modeling and molecular docking investigation. Byler KG, Collins JT, Ogungbe IV, Setzer WN. Comput Biol Chem 64 163-184 (2016)
  25. Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches. Nguyen PT, Yu H, Keller PA. J. Mol. Graph. Model. 57 1-8 (2015)
  26. Inhibition of host protein synthesis by Sindbis virus: correlation with viral RNA replication and release of nuclear proteins to the cytoplasm. Sanz MA, García-Moreno M, Carrasco L. Cell. Microbiol. 17 520-541 (2015)
  27. Full length and protease domain activity of chikungunya virus nsP2 differ from other alphavirus nsP2 proteases in recognition of small peptide substrates. Saisawang C, Sillapee P, Sinsirimongkol K, Ubol S, Smith DR, Ketterman AJ. Biosci. Rep. 35 (2015)
  28. Structural analyses of a constitutively active mutant of exchange protein directly activated by cAMP. White MA, Li S, Tsalkova T, Mei FC, Liu T, Woods VL, Cheng X. PLoS ONE 7 e49932 (2012)
  29. Deciphering the Nucleotide and RNA Binding Selectivity of the Mayaro Virus Macro Domain. Tsika AC, Melekis E, Tsatsouli SA, Papageorgiou N, Maté MJ, Canard B, Coutard B, Bentrop D, Spyroulias GA. J Mol Biol 431 2283-2297 (2019)
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  31. Mutations in Hypervariable Domain of Venezuelan Equine Encephalitis Virus nsP3 Protein Differentially Affect Viral Replication. Meshram CD, Phillips AT, Lukash T, Shiliaev N, Frolova EI, Frolov I. J Virol 94 (2020)
  32. Benzamidine ML336 inhibits plus and minus strand RNA synthesis of Venezuelan equine encephalitis virus without affecting host RNA production. Skidmore AM, Adcock RS, Jonsson CB, Golden JE, Chung DH. Antiviral Res. 174 104674 (2020)
  33. Comparative Characterization of the Sindbis Virus Proteome from Mammalian and Invertebrate Hosts Identifies nsP2 as a Component of the Virion and Sorting Nexin 5 as a Significant Host Factor for Alphavirus Replication. Schuchman R, Kilianski A, Piper A, Vancini R, Ribeiro JMC, Sprague TR, Nasar F, Boyd G, Hernandez R, Glaros T. J. Virol. 92 (2018)
  34. Conformer and pharmacophore based identification of peptidomimetic inhibitors of chikungunya virus nsP2 protease. Dhindwal S, Kesari P, Singh H, Kumar P, Tomar S. J. Biomol. Struct. Dyn. 35 3522-3539 (2017)
  35. Novel Mutations in nsP2 Abolish Chikungunya Virus-Induced Transcriptional Shutoff and Make the Virus Less Cytopathic without Affecting Its Replication Rates. Akhrymuk I, Lukash T, Frolov I, Frolova EI. J. Virol. 93 (2019)
  36. Structural insights into RNA recognition by the Chikungunya virus nsP2 helicase. Law YS, Utt A, Tan YB, Zheng J, Wang S, Chen MW, Griffin PR, Merits A, Luo D. Proc. Natl. Acad. Sci. U.S.A. 116 9558-9567 (2019)
  37. Targeting the nsp2 Cysteine Protease of Chikungunya Virus Using FDA Approved Library and Selected Cysteine Protease Inhibitors. Kumar P, Kumar D, Giri R. Pathogens 8 (2019)
  38. Turnip yellow mosaic virus protease binds ubiquitin suboptimally to fine-tune its deubiquitinase activity. Fieulaine S, Witte MD, Theile CS, Ayach M, Ploegh HL, Jupin I, Bressanelli S. J Biol Chem 295 13769-13783 (2020)

Related citations provided by authors (1)

  1. Structural Basis of Substrate Specificity in Venezuelan Equine Encephalitis nsP2 Protease. Russo AT, White MA, Malmstrom R, Watowich SJ To be published -