4E78

Crystal structure of a product state assembly of HCV NS5B genotype 2a JFH-1 isolate with beta hairpin loop deletion bound to primer-template RNA with 3'-dG

Summary for 4E78

• Entry DOI: 10.2210/pdb4e78/pdb
• Related: 4E76 4E7A
• Descriptor: 5'-R(*U*AP*CP*CP*GP*(GDO))-3', PROTEIN (RNA-directed RNA polymerase) (3 entities in total)
• Functional Keywords: rdrp, loopless delta8, ternary complex, product complex, flaviviridae, hepatitis c virus, viral protein, transferase-rna complex, transferase/rna
• Biological source: Hepatitis C virus (HCV); More
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane ; Single-pass membrane protein . Core protein p19: Virion . Envelope glycoprotein E1: Virion membrane ; Single-pass type I membrane protein . Envelope glycoprotein E2: Virion membrane ; Single-pass type I membrane protein . p7: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Protease NS2-3: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Non-structural protein 5A: Host endoplasmic reticulum membrane ; Peripheral membrane protein . RNA-directed RNA polymerase: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein : Q99IB8
• Total number of polymer chains: 3
• Total formula weight: 67486.58

Authors

Edwards, T.E.,Mosley, R.T. (deposition date: 2012-03-16, release date: 2012-04-18, Last modification date: 2024-10-30)

Primary citation

Mosley, R.T.,Edwards, T.E.,Murakami, E.,Lam, A.M.,Grice, R.L.,Du, J.,Sofia, M.J.,Furman, P.A.,Otto, M.J.
Structure of hepatitis C virus polymerase in complex with primer-template RNA.
J.Virol., 86:6503-6511, 2012

PubMed Abstract: The replication of the hepatitis C viral (HCV) genome is accomplished by the NS5B RNA-dependent RNA polymerase (RdRp), for which mechanistic understanding and structure-guided drug design efforts have been hampered by its propensity to crystallize in a closed, polymerization-incompetent state. The removal of an autoinhibitory β-hairpin loop from genotype 2a HCV NS5B increases de novo RNA synthesis by >100-fold, promotes RNA binding, and facilitated the determination of the first crystallographic structures of HCV polymerase in complex with RNA primer-template pairs. These crystal structures demonstrate the structural realignment required for primer-template recognition and elongation, provide new insights into HCV RNA synthesis at the molecular level, and may prove useful in the structure-based design of novel antiviral compounds. Additionally, our approach for obtaining the RNA primer-template-bound structure of HCV polymerase may be generally applicable to solving RNA-bound complexes for other viral RdRps that contain similar regulatory β-hairpin loops, including bovine viral diarrhea virus, dengue virus, and West Nile virus.

PubMed: 22496223
DOI: 10.1128/JVI.00386-12

Experimental method

X-RAY DIFFRACTION (2.9 Å)