Sandbox WWC8: Difference between revisions
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== Introduction == | == Introduction == | ||
Viruses with anti-sense RNA genomes, such as the influenza virus carry three core polypeptides inside their viral capsids in order to successfully enter a host and initiate the [[viral replication cycle]https://en.wikipedia.org/wiki/Influenza#Replication]. Especially important for viral replication and coordination with the host cell's replication machinery is a protein able to bind single-strand RNA scripts (ssRNA), forming ribonucleoprotein complexes (RNPs). This protein is commonly referred to as nucleoprotein (NP). The NP binds and transports viral RNA scripts to and from the host cell nucleus for transcription, replication, and packaging into new virions. When NP binds RNA, it is structure specific but not sequence specific, meaning NP will bind only ssRNA but will bind any ss-RNA script, viral or non-viral. Beyond the transport function, NP is an essential mediator between host and virus and coordinates complex processes during viral replication . Due to its important function, NP is intensively studies as a potential drug target for antiviral pharmaceuticals [1][2]. | Viruses with anti-sense RNA genomes, such as the influenza virus carry three core polypeptides inside their viral capsids in order to successfully enter a host and initiate the [[viral replication cycle]https://en.wikipedia.org/wiki/Influenza#Replication]. Especially important for viral replication and coordination with the host cell's replication machinery is a protein able to bind single-strand RNA scripts (ssRNA), forming ribonucleoprotein complexes (RNPs). This protein is commonly referred to as nucleoprotein (NP). The NP binds and transports viral RNA scripts to and from the host cell nucleus for transcription, replication, and packaging into new virions. When NP binds RNA, it is structure specific but not sequence specific, meaning NP will bind only ssRNA but will bind any ss-RNA script, viral or non-viral. Beyond the transport function, NP is an essential mediator between host and virus and coordinates complex processes during viral replication . Due to its important function, NP is intensively studies as a potential drug target for antiviral pharmaceuticals [[[1]]][[[2]]]. | ||
== Structural Features == | == Structural Features == | ||
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The loop binding cavity may constitute a viable drug target as disruption of the homo-oligomerization process prevents the formation of functional RNPs [2][4]. Special focus lies on the disruption of the salt bridge between Arg 416 and Glu339 [4]. | The loop binding cavity may constitute a viable drug target as disruption of the homo-oligomerization process prevents the formation of functional RNPs [2][4]. Special focus lies on the disruption of the salt bridge between Arg 416 and Glu339 [4]. | ||
== References == | == References == | ||
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[[http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/0022-1317-83-4-723#tab2]] A. Portela, P. Digard, The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication, Journal of General Virology. 83 (2002) 723–734. doi:10.1099/0022-1317-83-4-723. | [[http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/0022-1317-83-4-723#tab2]] A. Portela, P. Digard, The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication, Journal of General Virology. 83 (2002) 723–734. doi:10.1099/0022-1317-83-4-723. | ||
[ | [[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957899/]] K. Das, J.M. Aramini, L.-C. Ma, R.M. Krug, E. Arnold, Structures of influenza A proteins and insights into antiviral drug targets, Nat Struct Mol Biol. 17 (2010) 530–538. doi:10.1038/nsmb.1779. | ||
[ | [[http://www.nature.com/nature/journal/v444/n7122/full/nature05379.html]] Q. Ye, R.M. Krug, Y.J. Tao, The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA, Nature. 444 (2006) 1078–1082. | ||
doi:10.1038/nature05379. | doi:10.1038/nature05379. | ||
[ | [[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2537428/]] A.K.-L. Ng, H. Zhang, K. Tan, Z. Li, J. Liu, P.K.-S. Chan, S.-M. Li, W.-Y. Chan, S.W.-N. Au, A. Joachimiak, T. Walz, J.-H. Wang, P.-C. Shaw, Structure of the influenza virus A H5N1 nucleoprotein: implications for RNA binding, oligomerization, and vaccine design, FASEB J. 22 (2008) 3638–3647. doi:10.1096/fj.08-112110. | ||
[ | [[http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/0022-1317-70-9-2421]] O. Kistner, K. Müller, C. Scholtissek, Differential phosphorylation of the nucleoprotein of influenza A viruses, Journal of General Virology. 70 (1989) 2421–2431. | ||
[ | [[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC110190/]] S.K. Biswas, P.L. Boutz, D.P. Nayak, Influenza Virus Nucleoprotein Interacts with Influenza Virus Polymerase Proteins, J Virol. 72 (1998) 5493–5501. | ||
[ | [[https://www.researchgate.net/profile/Pablo_Gastaminza/publication/8946291_Area_E._et_al._3D_structure_of_the_influenza_virus_polymerase_complex_localization_of_subunit_domains._Proc._Natl_Acad._Sci._USA_101_308-313/links/0f31753aca0c8c30d5000000.pdf]] E. Area, J. Martín-Benito, P. Gastaminza, E. Torreira, J.M. Valpuesta, J.L. Carrascosa, J. Ortín, 3D structure of the influenza virus polymerase complex: localization of subunit domains, Proceedings of the National Academy of Sciences. 101 (2004) 308–313. | ||
[ | [[http://aac.asm.org/content/57/5/2231.full]] N. Lejal, B. Tarus, E. Bouguyon, S. Chenavas, N. Bertho, B. Delmas, R.W.H. Ruigrok, C.D. Primo, A. Slama-Schwok, Structure-Based Discovery of the Novel Antiviral Properties of Naproxen against the Nucleoprotein of Influenza A Virus, Antimicrob. Agents Chemother. 57 (2013) 2231–2242. doi:10.1128/AAC.02335-12. | ||
[ | [[http://www.tandfonline.com/doi/full/10.1080/07391102.2014.979230]] B. Tarus, H. Bertrand, G. Zedda, C. Di Primo, S. Quideau, A. Slama-Schwok, Structure-based design of novel naproxen derivatives targeting monomeric nucleoprotein of Influenza A virus, Journal of Biomolecular Structure and Dynamics. 33 (2015) 1899–1912. doi:10.1080/07391102.2014.979230. | ||
[[http://www.jbc.org/content/285/37/28411.full]] S. Boivin, S. Cusack, R.W.H. Ruigrok, D.J. Hart, Influenza A Virus Polymerase: Structural Insights into Replication and Host Adaptation Mechanisms, J. Biol. Chem. 285 (2010) 28411–28417. doi:10.1074/jbc.R110.117531. | |||
[ | [[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC104467/]] P. Digard, D. Elton, K. Bishop, E. Medcalf, A. Weeds, B. Pope, Modulation of Nuclear Localization of the Influenza Virus Nucleoprotein through Interaction with Actin Filaments, J Virol. 73 (1999) 2222–2231. | ||
[12] G. Neumann, M.R. Castrucci, Y. Kawaoka, Nuclear import and export of influenza virus nucleoprotein., J. Virol. 71 (1997) 9690–9700. | [[http://jvi.asm.org/content/71/12/9690.full.pdf+html]] G. Neumann, M.R. Castrucci, Y. Kawaoka, Nuclear import and export of influenza virus nucleoprotein., J. Virol. 71 (1997) 9690–9700. | ||
