PDBsum entry 1w3c

Hydrolase

PDB id: 1w3c

Contents

Protein chains

174 a.a. *

13 a.a. *

Ligands

DN1

DN2

Waters ×196

* Residue conservation analysis

PDB id:

1w3c

Name:

Hydrolase

Title:

Crystal structure of the hepatitis c virus ns3 protease in complex with a peptidomimetic inhibitor

Structure:

Protease/helicase ns3 (p70). Chain: a, b. Fragment: protease, residues 305-491. Engineered: yes. Nonstructural protein ns4a (p4). Chain: c, d. Fragment: residues 956-967. Engineered: yes. Mutation: yes

Source:

Hepatitis c virus (isolate 1). Organism_taxid: 11104. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: expressed under t7 promoter, iptg induced. Synthetic: yes. Organism_taxid: 11104

Biol. unit:

Dimer (from PDB file)

Resolution:

2.30Å R-factor: 0.177 R-free: 0.240

Authors:

S.Di Marco,C.Volpari

Key ref:

J.M.Ontoria et al. (2004). The design and enzyme-bound crystal structure of indoline based peptidomimetic inhibitors of hepatitis C virus NS3 protease. J Med Chem, 47, 6443-6446. PubMed id: 15588076 DOI: 10.1021/jm049435d

Date:

14-Jul-04 Release date: 09-Dec-04

Protein chains

P26662  (POLG_HCVJA) -  Genome polyprotein from Hepatitis C virus genotype 1b (isolate Japanese)

Seq: 3010 a.a.

Struc: 174 a.a.*

Protein chains

P26662  (POLG_HCVJA) -  Genome polyprotein from Hepatitis C virus genotype 1b (isolate Japanese)

Seq: 3010 a.a.

Struc: 13 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chains A, B, C, D: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
• Enzyme class 2: Chains A, B, C, D: 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: Chains A, B, C, D: E.C.3.4.22.- - ?????
• Enzyme class 4: Chains A, B, C, D: E.C.3.6.1.15 - nucleoside-triphosphate phosphatase.
• Reaction: a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + phosphate + H⁺
• Enzyme class 5: Chains A, B, C, D: 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/jm049435d

J Med Chem 47:6443-6446 (2004)

PubMed id: 15588076

The design and enzyme-bound crystal structure of indoline based peptidomimetic inhibitors of hepatitis C virus NS3 protease.

J.M.Ontoria, S.Di Marco, I.Conte, M.E.Di Francesco, C.Gardelli, U.Koch, V.G.Matassa, M.Poma, C.Steinkühler, C.Volpari, S.Harper.

ABSTRACT

The design of a series of peptidomimetic inhibitors of the hepatitis C virus NS3 protease is described. These inhibitors feature an indoline-2-carboxamide as a novel heterocyclic replacement for the P3 amino acid residue and N-terminal capping group of tripeptide based inhibitors. The crystal structure of the ternary NS3/NS4A/inhibitor complex for the most active molecule in this series highlights its suitability as an N-terminal capping group of a dipeptide inhibitor of the NS3 protease.