PDBsum entry 2ax0

Transferase

PDB id: 2ax0

Contents

Protein chains

554 a.a. *

Ligands

SO4 ×7

_5X ×2

Waters ×862

* Residue conservation analysis

PDB id:

2ax0

Name:

Transferase

Title:

Hepatitis c virus ns5b RNA polymerase in complex with a covalent inhibitor (5x)

Structure:

Genome polyprotein. Chain: a, b. Fragment: ns5b RNA-directed RNA polymerase. Engineered: yes. Mutation: yes

Source:

Hepatitis c virus. Organism_taxid: 11103. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.00Å R-factor: 0.212 R-free: 0.238

Authors:

J.P.Powers,D.E.Piper,Y.Li,V.Mayorga,J.Anzola,J.M.Chen,J.C.Jaen,G.Lee, J.Liu,M.G.Peterson,G.R.Tonn,Q.Ye,N.P.Walker,Z.Wang

Key ref:

J.P.Powers et al. (2006). SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase. J Med Chem, 49, 1034-1046. PubMed id: 16451069 DOI: 10.1021/jm050859x

Date:

02-Sep-05 Release date: 24-Jan-06

Protein chains

P26663  (POLG_HCVBK) -  Genome polyprotein from Hepatitis C virus genotype 1b (isolate BK)

Seq: 3010 a.a.

Struc: 555 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
• Enzyme class 2: E.C.3.4.21.98 - hepacivirin.
• Reaction: Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1'.
• Enzyme class 3: E.C.3.4.22.- - ?????
• Enzyme class 4: E.C.3.6.1.15 - nucleoside-triphosphate phosphatase.
• Reaction: a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + phosphate + H⁺
• Enzyme class 5: E.C.3.6.4.13 - Rna helicase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm050859x

J Med Chem 49:1034-1046 (2006)

PubMed id: 16451069

SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase.

J.P.Powers, D.E.Piper, Y.Li, V.Mayorga, J.Anzola, J.M.Chen, J.C.Jaen, G.Lee, J.Liu, M.G.Peterson, G.R.Tonn, Q.Ye, N.P.Walker, Z.Wang.

ABSTRACT

Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochemical potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were determined by X-ray crystallography, and the inhibitors were found to bind in an allosteric binding site separate from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compounds in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.