PDBsum entry 4b6e

Hydrolase

PDB id: 4b6e

Contents

Protein chains

646 a.a.

Ligands

SO4 ×2

10L

Waters ×346

PDB id:

4b6e

Name:

Hydrolase

Title:

Discovery of an allosteric mechanism for the regulation of hcv ns3 protein function

Structure:

Non-structural protein 4a, serine protease ns3. Chain: a, b. Fragment: residues 1678-1689, residues 1029-1657. Synonym: ns4a, p8, hepacivirin, ns3p, p70. Engineered: yes

Source:

Hepatitis c virus (isolate bk). Organism_taxid: 11105. Strain: genotype 1b. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: rosetta 2.

Resolution:

2.46Å R-factor: 0.191 R-free: 0.257

Authors:

S.M.Saalau-Bethell,A.J.Woodhead,G.Chessari,M.G.Carr,J.Coyle,B.Graham, S.D.Hiscock,C.W.Murray,P.Pathuri,S.J.Rich,C.J.Richardson, P.A.Williams,H.Jhoti

Key ref:

S.M.Saalau-Bethell et al. (2012). Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function. Nat Chem Biol, 8, 920-925. PubMed id: 23023261

Date:

09-Aug-12 Release date: 03-Oct-12

Protein chains

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

Seq: 3010 a.a.

Struc: 646 a.a.*

* PDB and UniProt seqs differ at 8 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

Nat Chem Biol 8:920-925 (2012)

PubMed id: 23023261

Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function.

S.M.Saalau-Bethell, A.J.Woodhead, G.Chessari, M.G.Carr, J.Coyle, B.Graham, S.D.Hiscock, C.W.Murray, P.Pathuri, S.J.Rich, C.J.Richardson, P.A.Williams, H.Jhoti.

ABSTRACT

Here we report a highly conserved new binding site located at the interface between the protease and helicase domains of the hepatitis C virus (HCV) NS3 protein. Using a chemical lead, identified by fragment screening and structure-guided design, we demonstrate that this site has a regulatory function on the protease activity via an allosteric mechanism. We propose that compounds binding at this allosteric site inhibit the function of the NS3 protein by stabilizing an inactive conformation and thus represent a new class of direct-acting antiviral agents.