PDBsum entry 2qe5

Transferase

PDB id: 2qe5

Contents

Protein chains

559 a.a. *

Ligands

617

Waters ×6

* Residue conservation analysis

PDB id:

2qe5

Name:

Transferase

Title:

Structure of hcv ns5b bound to an anthranilic acid inhibitor

Structure:

RNA-directed RNA polymerase. Chain: a, b, c, d. Synonym: ns5b, p68. Engineered: yes

Source:

Hepatitis c virus subtype 1b. Organism_taxid: 31647. Strain: bk. Gene: ns5b. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.60Å R-factor: 0.218 R-free: 0.225

Authors:

R.Chopra,K.Svenson,J.Bard

Key ref:

T.Nittoli et al. (2007). Identification of anthranilic acid derivatives as a novel class of allosteric inhibitors of hepatitis C NS5B polymerase. J Med Chem, 50, 2108-2116. PubMed id: 17402724

Date:

22-Jun-07 Release date: 02-Oct-07

Protein chains

Q99AU2  (Q99AU2_9HEPC) -  Genome polyprotein from Hepatitis C virus subtype 1b

Seq: 3010 a.a.

Struc: 559 a.a.

Enzyme reactions

• Enzyme class 1: 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 2: E.C.3.6.1.15 - nucleoside-triphosphate phosphatase.
• Reaction: a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + phosphate + H⁺
• Enzyme class 3: 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

J Med Chem 50:2108-2116 (2007)

PubMed id: 17402724

Identification of anthranilic acid derivatives as a novel class of allosteric inhibitors of hepatitis C NS5B polymerase.

T.Nittoli, K.Curran, S.Insaf, M.DiGrandi, M.Orlowski, R.Chopra, A.Agarwal, A.Y.Howe, A.Prashad, M.B.Floyd, B.Johnson, A.Sutherland, K.Wheless, B.Feld, J.O'Connell, T.S.Mansour, J.Bloom.

ABSTRACT

A series of potent anthranilic acid-based inhibitors of the hepatitis C NS5B polymerase has been identified. The inhibitors bind to a site on NS5B between the thumb and palm regions adjacent to the active site as determined by X-ray crystallography of the enzyme-inhibitor complex. Guided by both molecular modeling and traditional SAR, the enzyme activity of the initial hit was improved by approximately 100-fold, yielding a series of potent and selective NS5B inhibitors with IC50 values as low as 10 nM. These compounds were also inhibitors of the HCV replicon in cultured HUH7 cells.