Skip to main content
SpringerLink
Log in

Viral RNA-Dependent RNA Polymerases: A Structural Overview

  • Chapter
  • First Online:
Virus Protein and Nucleoprotein Complexes

Part of the book series: Subcellular Biochemistry ((SCBI,volume 88))

Abstract

Most emerging and re-emerging human and animal viral diseases are associated with RNA viruses. All these pathogens, with the exception of retroviruses, encode a specialized enzyme called RNA-dependent RNA polymerase (RdRP), which catalyze phosphodiester-bond formation between ribonucleotides (NTPs) in an RNA template-dependent manner. These enzymes function either as single polypeptides or in complex with other viral or host components to transcribe and replicate the viral RNA genome. The structures of RdRPs and RdRP catalytic complexes, currently available for several members of (+) ssRNA, (−)ssRNA and dsRNA virus families, have provided high resolution snapshots of the functional steps underlying replication and transcription of viral RNA genomes and their regulatory mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ago H, Adachi T, Yoshida A, Yamamoto M et al (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure 7:1417–1426

    CAS  PubMed  Google Scholar 

  • Albertini AA, Wernimont AK, Muziol T, Ravelli RB, Clapier CRet al. (2006) Crystal structure of the rabies virus nucleoprotein-RNA complex. Science 313(5785):360–363

    Article  CAS  PubMed  Google Scholar 

  • Appleby TC, Luecke H, Shim JH, Wu JZ, Cheney IW et al (2005) Crystal structure of complete rhinovirus RNA polymerase suggests front loading of protein primer. J Virol 79(1):277–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Appleby TC, Perry JK, Murakami E, Barauskas O, Feng J et al (2015) Viral replication. Structural basis for RNA replication by the hepatitis C virus polymerase. Science 347(6223):771–775

    Article  CAS  PubMed  Google Scholar 

  • Bahar MW, Sarin LP, Graham SC, Pang J, Bamford DH et al (2013) Structure of a VP1-VP3 complex suggests how birnaviruses package the VP1 polymerase. J Virol 87(6):3229–3236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ball AL (2007) Virus replication strategies. In: Knipe DM, Howley PM (eds) Fields virology. Wolters Kluwer Health/ Lippincott Williams & Wilkins, Philadelphia, pp 119–140

    Google Scholar 

  • Bentham M, Holmes K, Forrest S, Rowlands DJ, Stonehouse NJ (2012) Formation of higher-order foot-and-mouth disease virus 3Dpol complexes is dependent on elongation activity. J Virol 86(4):2371–2374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brautigam CA, Steitz TA (1998) Structural and functional insights provided by crystal structures of DNA polymerases and their substrate complexes. Curr Opin Struct Biol 8(1):54–63

    Article  CAS  PubMed  Google Scholar 

  • Bressanelli S, Tomei L, Roussel A, Incitti I, Vitale RL et al (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. PNAS 96:13034–13099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bressanelli S, Tomei L, Rey FA, De Francesco R (2002) Structural analysis of the hepatitis C virus RNA polymerase in complex with ribonucleotides. J Virol 76:3482–3492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruenn JA (2003) A structural and primary sequence comparison of the viral RNA-dependent RNA polymerases. Nucleic Acids Res 31:1821–1829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bussetta C, Choi KH (2012) Dengue virus nonstructural protein 5 adopts multiple conformations in solution. Biochemistry 51:5921–5931

    Article  CAS  PubMed  Google Scholar 

  • Butcher SJ, Grimes JM, Makeyev EV, Bamford DH, Stuart DI (2001) A mechanism for initiating RNA-dependent RNA polymerization. Nature 410(6825):235–240

    Article  CAS  PubMed  Google Scholar 

  • Campagnola G, Weygandt M, Scoggin K, Peersen O (2008) Crystal structure of coxsackievirus B3 3Dpol highlights the functional importance of residue 5 in picornavirus polymerases. J Virol 82(19):9458–9464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castro C, Smidansky ED, Arnold JJ, Maksimchuk KR, Moustafa I et al (2009) Nucleic acid polymerases use a general acid for nucleotidyl transfer. Nat Struct Mol Biol 16:212–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Çevik B, Holmes DE, Vrotsos E, Feller JA, Smallwood S et al (2004) The phosphoprotein (P) and L binding sites reside in the N-terminus of the L subunit of the measles virus RNA polymerase. Virology 327:297–306

    Article  PubMed  CAS  Google Scholar 

  • Çevik B, Smallwood S, Moyer SA (2007) Two N-terminal regions of the Sendai virus L RNA polymerase protein participate in oligomerization. Virology 363:189–197

    Article  PubMed  CAS  Google Scholar 

  • Chang S, Sun D, Liang H, Wang J, Li J et al (2015) Cryo-EM structure of influenza virus RNA polymerase complex at 4.3 Å resolution. Mol Cell 57:925–935

    Article  CAS  PubMed  Google Scholar 

  • Chen C, Wang Y, Shan C, Sun Y, Xu P et al (2013) Crystal structure of enterovirus 71 RNA-dependent RNA polymerase complexed with its protein primer VPg: implication for a trans mechanism of VPg uridylylation. J Virol 87(10):5755–5768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng Y (2015) Single-particle Cryo-EM at crystallographic resolution. Cell 161:450–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chinnaswamy S, Murali A, Li P, Fujisaki K, Kao CC (2010) Regulation of de novo-initiated RNA synthesis in hepatitis C virus RNA-dependent RNA polymerase by intermolecular interactions. J Virol 84:5923–5935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi KH, Groarke JM, Young DC, Kuhn RJ, Smith JL et al (2004) The structure of the RNA-dependent RNA polymerase from bovine viral diarrhea virus establishes the role of GTP in de novo initiation. PNAS 101:4425–4430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi KH, Gallei A, Becher P, Rossmann MG (2006) The structure of bovine viral diarrhea virus RNA-dependent RNA polymerase and its amino-terminal domain. Structure 14:1107–1113

    Article  CAS  PubMed  Google Scholar 

  • Choi KH, Rossmann MG (2009) RNA-dependent RNA polymerases from Flaviviridae. Curr Opin Struct Biol 19:746–751

    Article  CAS  PubMed  Google Scholar 

  • Clemente-Casares P, López-Jiménez AJ, Bellón-Echeverría I, Encinar JA, Martínez-Alfaro E et al (2011) De novo polymerase activity and Oligomerization of hepatitis C virus RNA-dependent RNA-polymerases from genotypes 1 to 5. PLoS One 6(4):e18515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collier AM, Lyytinen OL, Guo YR, Toh Y, Poranen MM et al (2016) Initiation of RNA polymerization and polymerase Encapsidation by a small dsRNA virus. PLoS Pathog 12(4):e1005523

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Das K, Arnold E (2015) Negative-strand RNA virus L proteins: one machine, many activities. Cell 162(2):239–241

    Article  CAS  PubMed  Google Scholar 

  • Davidson AD (2009) Chapter 2 new insights into Flavivirus nonstructural protein 5. In: Maramorosch K, Shatkin AJ, Purphy FA (eds) Advances in virus research, Vol 74. Elsevier Inc., pp 41–101

    Google Scholar 

  • den Boon J, Diaz A, Alquist P (2010) Cytoplasmic vial replication complexes. Cell Host Microbe 8(1):77–85

    Article  CAS  Google Scholar 

  • Deval J, Jin Z, Chuang YC, Kao CC (2017) Structure(s), function(s), and inhibition of the RNA-dependent RNA polymerase of noroviruses. Virus Res 234:21–33

    Article  CAS  PubMed  Google Scholar 

  • Estes MK, Kapikian AZ (2007) Rotaviruses. In: Knipe DM, Howley PM (eds) Fields virology pp. 1917–1974. Wolters Kluwer Health/ Lippincott Williams & Wilkins. Philadelphia

    Google Scholar 

  • Estrozi LF, Settembre EC, Goret G, McClain B, Zhang X et al (2013) Location of the dsRNA-DependentPolymerase, VP1, in Rotavirus Particles. J MolBiol 425:124–132

    Article  CAS  Google Scholar 

  • Ferrer-Orta C, Arias A, Perez-Luque R, Escarmís C, Domingo E et al (2004) Structure of foot-and-mouth disease virus RNA-dependent RNA polymerase and its complex with a template-primer RNA. J Biol Chem 279(45):47212–47221

    Article  CAS  PubMed  Google Scholar 

  • Ferrer-Orta C, Arias A, Escarmís C, Verdaguer N (2006a) A comparison of viral RNA-dependent RNA polymerases. Curr Opin Struct Biol 16:27–34

    Article  CAS  PubMed  Google Scholar 

  • Ferrer-Orta C, Arias A, Agudo R, Pérez-Luque R, Escarmís C et al (2006b) The structure of a protein primer-polymerase complex in the initiation of genome replication. EMBO J 25(4):880–888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferrer-Orta C, Arias A, Pérez-Luque R, Escarmís C, Domingo E et al (2007) Sequential structures provide insights into the fidelity of RNA replication. Proc Natl Acad Sci U S A 104(22):9463–9468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferrer-Orta C, Verdaguer N (2009) Chapter 18 RNA virus polymerases. In: Cameron CE, Götte M, Raney KD (eds) Viral genome replication. Springer Inc, pp 383–401

    Google Scholar 

  • Ferrero DS, Buxaderas M, Rodriguez JF, Verdaguer N (2015) The structure of the RNA-dependent RNA polymerase of a Permutotetravirus suggests a link between primer-dependent and primer-independent polymerases. PLoS Pathog 11(12):e1005265

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Forss S, Schaller H (1982) A tandem repeat gene in a picornavirus. Nucleic Acids Res 10(20):6441–6450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garriga D, Navarro A, Querol-Audi J, Abaitua F et al (2007) Activation mechanism of a noncanonical RNA-dependent RNA polymerase. Proc Natl Acad Sci U S A 104(51):20540–20545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garriga D, Ferrer-Orta C, Querol-Audí J, Oliva B, Verdaguer N (2013) Role of motif B loop in allosteric regulation of RNA-dependent RNA polymerization activity. J Mol Biol 425(13):2279–2287

    Article  CAS  PubMed  Google Scholar 

  • Gerlach P, Malet H, Cusack S, Reguera J (2015) Structural insights into Bunyavirus replication and its regulation by the vRNA promoter. Cell 161:1267–1279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Godoy AS, Lima GM, Oliveira KI, Torres NU, Maluf FV et al (2017) Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase. Nat Commun 8:14764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gohara DW, Arnold JJ, Cameron CE (2004) Poliovirus RNA-dependent RNA polymerase (3Dpol): kinetic, thermodynamic, and structural analysis of Ribonucleotide selection. Biochemistry 43(18):5149–5158

    Article  CAS  PubMed  Google Scholar 

  • Gong P, Peersen OB (2010) Structural basis for active site closure by the poliovirus RNA-dependent RNA polymerase. Proc Natl Acad Sci U S A 107(52):22505–22510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gong P, Kortus MG, Nix JC, Davis RE, Peersen OB (2013) Structures of coxsackievirus, rhinovirus, and poliovirus polymerase elongation complexes solved by engineering RNA mediated crystal contacts. PLoS One 8(5):e60272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodfellow I (2011) The genome-linked protein VPg of vertebrate viruses – a multifaceted protein. Curr Opin Virol 1(5):355–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorbalenya AE, Pringle FM, Zeddam JL, Luke BT, Cameron CE et al (2002) The palm subdomain-based active site is internally permuted in viral RNA-dependent RNA polymerases of an ancient lineage. J Mol Biol 324:47–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graham SC, Sarin LP, Bahar MW, Myers RA, Stuart DIet al. (2011) The N-terminus of the RNA polymerase from infectious pancreatic necrosis virus is the determinant of genome attachment. PLoS Pathog 7:e1002085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Green TJ, Zhang X, Wertz GW, Luo M (2006) Structure of the vesicular stomatitis virus nucleoprotein-RNA complex. Science 313(5785):357–360

    Article  CAS  PubMed  Google Scholar 

  • Gridley C, Patton J (2014) Regulation of rotavirus polymerase activity by inner capsid proteins. Curr Opin Virol 9:31–38

    Article  CAS  PubMed  Google Scholar 

  • Gruez A, Selisko B, Roberts M, Bricogne G, Bussetta C et al (2008) The crystal structure of coxsackievirus B3 RNA-dependent RNA polymerase in complex with its protein primer VPg confirms the existence of a second VPg binding site on Picornaviridae polymerases. J Virol 82(19):9577–9590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hansen JL, Long AM, Schultz SC (1997) Structure of the RNA-dependent RNA polymerase of poliovirus. Structure 5:1109–1122

    Article  CAS  PubMed  Google Scholar 

  • Harak C, Lohmann V (2015) Ultrastructure of the replication sites of positive-strand RNA viruses. Virology 479:418–433

    Article  PubMed  CAS  Google Scholar 

  • Hengrung N, EI Omari K, Serna Martin I, Vreede FT, Cusack S et al (2015) Crystal structure of the RNA-dependent RNA polymerase from influenza C virus. Nature 527(7576):114–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hobson SD, Rosenblum ES, Richards OC, Richmond K, Kirkegaard K et al (2001) Oligomeric structures of poliovirus polymerase are important for function. EMBO J 20:1153–1163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Högbom M, Jager K, Robel I, Unge T, Rohayem J (2009) The active form of the norovirus RNA-dependent RNA polymerase is a homodimer with cooperative activity. J Gen Virol 90:281–291

    Article  PubMed  CAS  Google Scholar 

  • Huang H, Chopra R, Verdine GL, Harrison SC (1998) Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 282:1669–1675

    Article  CAS  PubMed  Google Scholar 

  • Ilca SL, Kotecha A, Sun X, Poranen MM, Stuart DI et al (2015) Localized reconstruction of subunits from electron cryomicroscopy images of macromolecular complexes. Nat Commun 6:8843

    Article  PubMed  CAS  Google Scholar 

  • Jackson RJ, Howell MT, Kaminski A (1990) The novel mechanism of initiation of picornavirus RNA translation. Trends Biochem Sci 15:477–483

    Article  PubMed  Google Scholar 

  • Kaiser WJ, Chaudhry Y, Sosnovtsev SV, Goodfellow IG (2006) Analysis of protein-protein interactions in the feline calicivirus replication complex. J Gen Virol 87:363–368

    Article  CAS  PubMed  Google Scholar 

  • Kao CC, Singh P, Ecker DJ (2001) De novo initiation of viral RNA-dependent RNA synthesis. Virology 287(2):251–260

    Article  CAS  PubMed  Google Scholar 

  • King AMQ, Sangar DV, Harris TJR, Brown F (1980) Heterogeneity of the genome-linked protein of foot-and-mouth disease virus. Virol 34:627–634

    Article  CAS  Google Scholar 

  • Klema VJ, Ye M, Hindupur A, Teramoto T, Gottipati K et al (2016) Dengue virus nonstructural protein 5 (NS5) assembles into a dimer with a unique Methyltransferase and polymerase Interface. PLoS Pathog 12(2):e1005451

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lai VC, Kao CC, Ferrari E, Park J, Uss AS et al (1999) Mutational analysis of bovine viral diarrhea virus RNA-dependent RNA polymerase. J Virol 73:10129–10136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le Breton M, Meyniel-Schicklin L, Deloire A, Coutard B, Canard B et al (2011) Flavivirus NS3 and NS5 proteins interaction network: a high-throughput yeast two-hybrid screen. BMC Microbiol 11:234

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee J, Alam I, Han KR, Cho S, Shin S et al (2011) Crystal structure of murine norovirus-1 RNA-dependent RNA polymerase. J General Virology 92:1607–1616

    Article  CAS  Google Scholar 

  • Lesburg CA, Cable MB, Ferrari E, Hong Z, Mannarino AF et al (1999) Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat Struct Biol 6:937–943

    Article  CAS  PubMed  Google Scholar 

  • Lescar J, Canard B (2009) RNA-dependent RNA polymerases from flaviviruses and Picornaviridae. Curr Opin Struct Biol 19(6):759–767

    Article  CAS  PubMed  Google Scholar 

  • Li J, Rahmeh A, Morelli M, Whelan SP (2008) A conserved motif in region v of the large polymerase proteins of nonsegmented negative-sense RNA viruses that is essential for mRNA capping. J Virol 82:775–784

    Article  CAS  PubMed  Google Scholar 

  • Li X, Zhou N, Chen W, Zhu B, Wang X et al (2017) Near-atomic resolution structure determination of a Cypovirus capsid and polymerase complex using Cryo-EM at 200kV. J Mol Biol 429(1):79–87

    Article  CAS  PubMed  Google Scholar 

  • Liang B, Li Z, Jenni S, Rahmeh AA, Morin BM et al (2015) Structure of the L protein of vesicular stomatitis virus from electron Cryomicroscopy. Cell 162:314–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim SP, Koh JHK, Seh CC, Liew CW, Davidson AD et al (2013) A crystal structure of the dengue virus non-structural protein 5 (NS5) polymerase delineates interdomain amino acid residues that enhance its thermostability and de novo initiation activities. J Biol Chem 288:31105–31114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu H, Cheng L (2015) Cryo-EM shows thepolymerasestructures and a nonspooledgenomewithin a dsRNA virus. Science 349(6254):1347–1350

    Article  CAS  PubMed  Google Scholar 

  • Love RA, Maegley KA, Yu X, Ferre RA, Lingardo LK et al (2004) The crystal structure of the RNA-dependent RNA polymerase from human rhinovirus: a dual function target for common cold antiviral therapy. Structure 12(8):1533–1544

    Article  CAS  PubMed  Google Scholar 

  • Lu G, Gong P (2013) Crystal structure of the full-length Japanese encephalitis virus NS5 reveals a conserved methyltransferase-polymerase interface. PLoS Pathog 9(8):e1003549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu X, Mc Donald SM, Tortorici MA, Tao YJ, Vasquez-Del Carpio R et al (2008) Mechanism for coordinated RNA packaging and genome replication by rotavirus polymerase VP1. Structure 16(11):1678–1688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luque D, Rivas G, Alfonso C, Carrascosa JL, Rodriguez JF et al (2009a) Infectious bursal disease virus is an icosahedral polyploid dsRNA virus. PNAS 106(7):2148–2152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luque D, Saugar I, Rejas MT, Carrascosa JL, Rodriguez JF et al (2009b) Infectious bursal disease virus: ribonucleoprotein complexes of a double-stranded RNA virus. J Mol Biol 386(3):891–901

    Article  CAS  PubMed  Google Scholar 

  • Lyle JM, Clewell A, Richmond K, Richards OC, Hope DA et al (2002) Similar structural basis for membrane localization and protein priming by an RNA-dependent RNA polymerase. J Biol Chem 277(18):16324–16331

    Article  CAS  PubMed  Google Scholar 

  • Mairiang D, Zhang H, Sodja A, Murali T, Suriyaphol P et al (2013) Identification of new protein interactions between dengue fever virus and its hosts, human and mosquito. PLoS One 8(1):e53535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malet H, Egloff MP, Selisko B, Butcher RE, Wright PJ et al (2007) Crystal structure of the RNA polymerase domain of the West Nile virus non-structural protein 5. J Biol Chem 282(14):10678–10689

    Article  CAS  PubMed  Google Scholar 

  • Marcotte LL, Wass AB, Gohara DW, Pathak HB, Arnold JJ et al (2007) Crystal structure of poliovirus 3CD protein: virally encoded protease and precursor to the RNA-dependent RNA polymerase. J Virol 81:3583–3596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mas A, Clemente-Casares P, Ramirez E, Sabariegos R (2016) The HCV replicase interactome. American JVirol 5(1):8–14

    Google Scholar 

  • McDonald SM, Tao YJ, Patton JT (2009) The ins and outs of four-tunneled RNA-dependent RNA polymerases. Curr Opin Struct Biol 19(6):775–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mosley RT, Edwards TE, Murakami E, Lam AM, Grice RL et al (2012) Structure of hepatitis C virus polymerase in complex with primer-template RNA. J Virol 86:6503–6511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura T, Zhao Y, Yamagata Y, Hua YJ, Yang W (2012) Watching DNA polymerase η make a phosphodiester bond. Nature 487:196–201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ng KK, Cherney MM, Vazquez AL, Machin A, Alonso JM et al (2002) Crystal structures of active and inactive conformations of a caliciviral RNA-dependent RNA polymerase. J Biol Chem 277(2):1381–1387

    Article  CAS  PubMed  Google Scholar 

  • Ng KK, Pendás-Franco N, Rojo J, Boga JA, Machín A et al (2004) Crystal structure of norwalk virus polymerase reveals the carboxyl terminus in the active site cleft. J Biol Chem 279(16):16638–16645

    Article  CAS  PubMed  Google Scholar 

  • O’Reilly EK, Kao CC (1998) Analysis of RNA-dependent RNA polymerase structure and function as guided by known polymerase structures and computer predictions of secondary structure. Virology 252:287–303

    Article  PubMed  Google Scholar 

  • Ogino T, Banerjee AK (2007) Unconventional mechanism of mRNA capping by the RNA-dependent RNA polymerase of vesicular stomatitis virus. Mol Cell 25(1):85–97

    Article  CAS  PubMed  Google Scholar 

  • Pan J, Vakharia VN, Tao YJ (2007) Structural of a birnavirus polymerase reveals a distinct active site topology. Proc Natl Acad Sci U S A 104:7385–7390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pathak HB, Oh HS, Goodfellow IG, Arnold JJ, Cameron CE (2008) Picornavirus genome replication: roles of precursor proteins and rate-limiting steps in oriI-dependent VPg uridylylation. J Biol Chem 283:30677–30688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pata JD, Schultz SC, Kirkegaard K (1995) Functional oligomerization of poliovirus RNA-dependent RNA polymerase. RNA 5:466–477

    Google Scholar 

  • Patton JT, Jones MT, Kalbach AN, He YW, Xiaobo J (1997) Rotavirus RNA polymerase requires the core shell protein to synthesize the double-stranded RNA genome. J Virol 71:9618–9626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paul AV, van Boom JH, Filippov D, Wimmer E (1998) Protein-primed RNA synthesis by purified poliovirus RNA polymerase. Nature 393:280–284

    Article  CAS  PubMed  Google Scholar 

  • Paul AV, Peters J, Mugavero J, Yin J, van Boom JH et al (2003) Biochemical and genetic studies of the VPg uridylylation reaction catalyzed by the RNA polymerase of poliovirus. J Virol 77(2):891–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paul AV, Wimmer E (2015) Initiation of protein-primed picornavirus RNA synthesis. Virus Res 206:12–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peersen OB (2017) Picornaviral polymerase structure, function, and fidelity modulation. Virus Res 234:4–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pflug A, Guilligay D, Reich S, Cusack S (2014) Structure of influenza a polymerase bound to the viral RNA promoter. Nature 516:355–360

    Article  CAS  PubMed  Google Scholar 

  • Plotch SJ, Bouloy M, Ulmanen I, Krug RM (1981) A unique cap(mGpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription. Cell 23(3):847–858

    Article  CAS  PubMed  Google Scholar 

  • Potisopon S, Priet S, Collet A, Decroly E, Canard B et al (2014) The methytransferase domain of the dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain. Nucleic Acids Res 42(18):11642–11656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rahmeh AA, Schenk AD, Danek EI, Kranzuch PJ, Liang B et al (2010) Molecular architecture of the vesicular stomatitis virus RNA polymerase. Proc Natl Acad Sci U S A 107(46):20075–20080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reguera J, Gerlach P, Cusack S (2016) Towards a structural understanding of RNA synthesis by negative strand RNA viral polymerases. Curr Opin Struct Biol 36:75–84

    Article  CAS  PubMed  Google Scholar 

  • Reich S, Guilligay D, Pflug A, Alexander MH, Berger I et al (2014) Structural insight into cap-snatching and RNA synthesis by influenza polymerase. Nature 516(7531):361–366

    Article  CAS  PubMed  Google Scholar 

  • Ren Z, C Franklin M, Ghose R (2013) Structure of the RNA-directed RNA polymerase from the cystovirus φ12. Proteins, 81(8):1479–1484

    Article  CAS  Google Scholar 

  • Salgado PS, Makeyev EV, Butcher SJ, Bamford DH, Stuart DI et al (2004) The structural basis for RNA specificity and Ca2+ inhibition of an RNA-dependent RNA polymerase. Structure 12(2):307–316

    CAS  PubMed  Google Scholar 

  • Saw WG, Tria G, Gruber A, Subramanian Manimekalai MS, Zhao Y, Chandramohan A et al (2015) Structural insight and flexible features of NS5 proteins from all four serotypes of dengue virus in solution. Acta Cryst D71:2309–2327

    Google Scholar 

  • Schiff LA, Nibert ML, Tyler KL (2007) Orthoreoviruses and their replication. In: Knipe DM, Howley PM (eds) Fields virology. Wolters Kluwer Health/ Lippincott Williams & Wilkins, Philadelphia, pp 1853–1916

    Google Scholar 

  • Selisko B, Wang C, Harris E, Canard B (2014) Regulation of Flavivirus RNA synthesis and replication. Curr Opin Virol 0:74–83

    Article  CAS  PubMed Central  Google Scholar 

  • Shen H, Sun H, Li G (2012) What is the role of motif D in the nucleotide incorporation catalyzed by the RNA-dependent RNA polymerase from poliovirus? PLoS Comput Biol 8(12):e1002851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sholders AJ, Peersen OB (2014) Distinct conformations of a putative translocation element in poliovirus polymerase. J Mol Biol 426(7):1407–1419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shu B, Gong P (2016) Structural basis of viral RNA-dependent RNA polymerase catalysis and translocation. PNAS 113(28):E4005–E4014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smallwood S, Hovel T, Neubert WJ, Moyer SA (2002) Different substitutions at conserved amino acids in domains II and III in the Sendai L RNA polymerase protein inactivate viral RNA synthesis. Virology 304:135–145

    Article  CAS  PubMed  Google Scholar 

  • Smallwood S, Moyer SA (2004) The L polymerase protein of parainfluenza virus 3 forms an oligomer and can interact with the heterologous Sendai virus L, P and C proteins. Virology 318:439–450

    Article  CAS  PubMed  Google Scholar 

  • Spagnolo JF, Rossignol E, Bullitt E, Kirkegaard K (2010) Enzymatic and nonenzymatic functions of viral RNA-dependent RNA polymerases within oligomeric arrays. RNA 16:382–393

    Article  PubMed  PubMed Central  Google Scholar 

  • Steitz TA (1998) A mechanism for all polymerases. Nature 391(6664):231–232

    Article  CAS  PubMed  Google Scholar 

  • Subramanian Manimekalai MS, Saw WG, Pan A, Gruber A, Gruber G (2016) Identification of the critical linker residues conferring differences in the compactness of NS5 from dengue virus serotype 4 and NS5 from dengue virus serotypes 1–3. Acta Cryst D72:795–807

    Google Scholar 

  • Surana P, Satchidanandam V, Nair DT (2014) RNA-dependent RNA polymerase of Japanese encephalitis virus binds the initiator nucleotide GTP to form a mechanistically important pre-initiation state. Nucleic Acids Res 42(4):2758–2773

    Article  CAS  PubMed  Google Scholar 

  • Tao L, Farsetta DL, Nibert ML, Harrison SC (2002) RNA Synthesis in a Cage—structural studies of reovirus polymerase λ3. Cell, 111:733–745

    Article  CAS  PubMed  Google Scholar 

  • Tay MYF, Smith K, Ng IHW, Chan KWK, Zhao Y et al (2016) The C-terminal 18 amino acid region of dengue virus NS5 regulates its subcellular localization and contains a conserved arginine residue essential for infectious virus production. PLoS Pathog 12(9):e1005886

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • te Velthuis AJW (2014) Common and unique features of viral RNA-dependent polymerase. Cell Mol Life Sci 71:4403–4420

    Article  CAS  Google Scholar 

  • te Velthuis AJW, Fodor E (2016) Influenza virus RNA polymerase: insights into the mechanisms of viral RNA synthesis. Nat Rev Microbiol 14:479–493

    Article  CAS  Google Scholar 

  • Tellez AB, Wang J, Tanner EJ, Spagnolo JF, Kirkegaard K et al (2011) Interstitial contacts in an RNA-dependent RNA polymerase lattice. J Mol Biol 412:737–750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thompson AA, Peersen OB (2004) Structural basis for proteolysis-dependent activation of the poliovirus RNA-dependent RNA polymerase. EMBO J 23:3462–3471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thompson AA, Albertini RA, Peersen OB (2007) Stabilization of poliovirus polymerase by NTP binding and fingers-thumb interactions. J Mol Biol 366:1459–1474

    Article  CAS  PubMed  Google Scholar 

  • Tortorici MA, Broering TJ, Nibert ML, Patton JT (2003) Template recognition and formation of initiation complexes by the replicase of a segmented double-stranded RNA virus. J Biol Chem 278:32673–32682

    Article  CAS  PubMed  Google Scholar 

  • Upadhyay AK, Cyr M, Longenecker K, Tripathi R, Sun C, Kempf DL (2017) Crystal structure of full-length Zika virus NS5 protein reveals a conformation similar to Japanese encephalitis virus NS5. Acta Cryst F 73:116–122

    Article  CAS  Google Scholar 

  • van Dijk AA, Makeyev EV, Bamford DH (2004) Initiation of viral RNA-dependent RNA polymerization. J Gen Virol 85(5):1077–1093

    Article  PubMed  CAS  Google Scholar 

  • Verdaguer N, Ferrer-Orta C (2012) Conformational changes in motif D of RdRPs as fidelity determinant. Structure 20(9):1448–1450

    Article  CAS  PubMed  Google Scholar 

  • Vives-Adrian L, Lujan C, Oliva B, van der Linden L, Selisko B et al (2014) The crystal structure of a cardiovirus RNA-dependent RNA polymerase reveals an unusual conformation of the polymerase active site. J Virol 88(10):5595–5607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang C, Wang C, Li Q, Wang Z, Xie W (2017) Crystal structure and thermostability characterization of EV-D68-3Dpol. J Virol, JVI:00876–00817

    Google Scholar 

  • Wang J, Lyle JM, Bullitt E (2013) Surface for catalysis by poliovirus RNA-dependent RNA polymerase. J Mol Biol 425:2529–2540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang QM, Hockman MA, Staschke K, Johnson RB, Case KA et al (2002) Oligomerization and cooperative RNA synthesis activity of hepatitis C virus RNA-dependent RNA polymerase. J Virol 76(8):3865–3872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Y, Lou Z, Miao Y, Yu Y, Dong H et al (2010) Structures of EV71 RNA-dependent RNA polymerase in complex with substrate and analogue provide a drug target against the hand-foot-and-mouth disease pandemic in China. Protein Cell 1(5):491–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang X, Smidansky ED, Maksimchuk KR, Lum D, Welch JL et al (2012) Motif D of viral RNA-dependent RNA polymerases determines efficiency and fidelity of nucleotide addition. Structure 20(9):1519–1527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yap TL, Xu T, Chen YL, Malet H, Egloff MP et al (2007) Crystal structure of the dengue virus RNA-dependent RNA polymerase catalytic domain at 1.85-angstrom resolution. J Virol 81(9):4753–4765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zamoto-Niikura A, Terasaki K, Ikegami T, Peters CJ, Makino S (2009) Rift valley fever virus L protein forms a biologically active oligomer. J Virol 83:12779–12789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zamyatkin DF, Parra F, Alonso JM, Harki DA, Peterson BR et al (2008) Structural insights into mechanisms of catalysis and inhibition in Norwalk virus polymerase. J Biol Chem 283(12):7705–7712

    Article  CAS  PubMed  Google Scholar 

  • Zeddam JL, Gordon KH, Lauber C, Alves CA, Luke BT et al (2010) Euprosterna elaeasa virus genome sequence and evolution of the Tetraviridae family: emergence of bipartite genomes and conservation of the VPg signal with the dsRNA Birnaviridae family. Virology 397:145–154

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Walker SB, Chipman PR, Nibert ML et al (2003) Virus polymerase λ3 localized by cryo-electron microscopy of virions at a resolution of 7.6 Å. Nature StrucBiol 10(12):1011–1018

    CAS  Google Scholar 

  • Zhang X, Ding K, Yu X, Chang W, Sun J et al (2015) In situ structures of the segmented genome and RNA polymerase complex inside a dsRNA virus. Nature 527:531–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Soh TS, Lim SP, Chung KY, Swaminathan K et al (2015a) Molecular basis for specific viral RNA recognition and 2'-O-ribose methylation by the dengue virus nonstructural protein 5 (NS5). Proc Natl Acad Sci U S A 112(48):14834–14839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Soh TS, Zheng J, Chan KWK, Phoo WWet al. (2015b) A crystal structure of the dengue virus NS5 protein reveals a novel inter-domain interface essential for protein flexibility and virus replication. PLoS Pathog 11(3):e1004682

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

We acknowledge the funding from the Spanish Ministry of Economy Industry and Competitiveness (BIO2014-54588-P and Maria de Maeztu action MDM-2014-0435).

Author information

Authors and Affiliations

  1. Structural Biology Unit, Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Barcelona, Spain

    Diego Ferrero, Cristina Ferrer-Orta & Núria Verdaguer

Authors
  1. Diego Ferrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristina Ferrer-Orta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Núria Verdaguer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Núria Verdaguer .

Editor information

Editors and Affiliations

  1. Institute of Zoology, University of Mainz, Mainz, Germany

    J. Robin Harris

  2. MRC-University of Glasgow Centre for Virus Research, Glasgow, UK

    David Bhella

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ferrero, D., Ferrer-Orta, C., Verdaguer, N. (2018). Viral RNA-Dependent RNA Polymerases: A Structural Overview. In: Harris, J., Bhella, D. (eds) Virus Protein and Nucleoprotein Complexes. Subcellular Biochemistry, vol 88. Springer, Singapore. https://doi.org/10.1007/978-981-10-8456-0_3

Download citation

Publish with us

Policies and ethics

Search

Navigation