1YUY

HEPATITIS C VIRUS NS5B RNA-DEPENDENT RNA POLYMERASE GENOTYPE 2a

Summary for 1YUY

• Entry DOI: 10.2210/pdb1yuy/pdb
• Descriptor: RNA-Dependent RNA polymerase, SULFATE ION (3 entities in total)
• Functional Keywords: ns5b polymerase genotype 2a, viral protein
• Biological source: Hepatitis C virus
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein (By similarity). Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): P26660
• Total number of polymer chains: 1
• Total formula weight: 63759.96

Authors

Biswal, B.K.,Cherney, M.M.,Wang, M.,Chan, L.,Yannopoulos, C.G.,Bilimoria, D.,Nicolas, O.,Bedard, J.,James, M.N.G. (deposition date: 2005-02-14, release date: 2005-03-22, Last modification date: 2024-02-14)

Primary citation

Biswal, B.K.,Cherney, M.M.,Wang, M.,Chan, L.,Yannopoulos, C.G.,Bilimoria, D.,Nicolas, O.,Bedard, J.,James, M.N.G.
Crystal structures of the RNA dependent RNA polymerase genotype 2a of hepatitis C virus reveal two conformations and suggest mechanisms of inhibition by non-nucleoside inhibitors.
J.Biol.Chem., 280:18202-18210, 2005

PubMed Abstract: Crystal structures of the RNA-dependent RNA polymerase genotype 2a of hepatitis C virus (HCV) from two crystal forms have been determined. Similar to the three-dimensional structures of HCV polymerase genotype 1b and other known polymerases, the structures of the HCV polymerase genotype 2a in both crystal forms can be depicted in the classical right-hand arrangement with fingers, palm, and thumb domains. The main structural differences between the molecules in the two crystal forms lie at the interface of the fingers and thumb domains. The relative orientation of the thumb domain with respect to the fingers and palm domains and the beta-flap region is altered. Structural analysis reveals that the NS5B polymerase in crystal form I adopts a "closed" conformation that is believed to be the active form, whereas NS5B in crystal form II adopts an "open" conformation and is thus in the inactive form. In addition, we have determined the structures of two NS5B polymerase/non-nucleoside inhibitor complexes. Both inhibitors bind at a common binding site, which is nearly 35 A away from the polymerase active site and is located in the thumb domain. The binding pocket is predominantly hydrophobic in nature, and the enzyme inhibitor complexes are stabilized by hydrogen bonding and van der Waals interactions. Inhibitors can only be soaked in crystal form I and not in form II; examination of the enzyme-inhibitor complex reveals that the enzyme has undergone a dramatic conformational change from the form I (active) complex to the form II (inactive).

PubMed: 15746101
DOI: 10.1074/jbc.M413410200

Experimental method

X-RAY DIFFRACTION (1.9 Å)