PDBsum entry 3zd0

Transport protein

PDB id: 3zd0

Contents

Protein chain

85 a.a.

PDB id:

3zd0

Name:

Transport protein

Title:

The solution structure of monomeric hepatitis c virus p7 yields potent inhibitors of virion release

Structure:

P7 protein. Chain: a. Fragment: residues 747-809. Engineered: yes. Other_details: flag tag at residues upto and including residue 18

Source:

Hepatitis c virus. Hcv. Organism_taxid: 11103. Strain: 1b. Variant: j4 isolate. Expressed in: escherichia coli. Expression_system_taxid: 469008.

NMR struc:

20 models

Authors:

T.L.Foster,G.Sthompson,A.P.Kalverda,J.Kankanala,J.Thompson, A.M.Barker,D.Clarke,M.Noerenberg,A.R.Pearson,D.J.Rowlands, S.W.Homans,M.Harris,R.Foster,S.D.C.Griffin

Key ref:

T.L.Foster et al. (2014). Structure-guided design affirms inhibitors of hepatitis C virus p7 as a viable class of antivirals targeting virion release. Hepatology, 59, 408-422. PubMed id: 24022996 DOI: 10.1002/hep.26685

Date:

23-Nov-12 Release date: 04-Sep-13

Protein chain

Q9WLK8  (Q9WLK8_9HEPC) -  Genome polyprotein (Fragment) from Hepacivirus hominis

Seq: 2864 a.a.

Struc: 85 a.a.*

* PDB and UniProt seqs differ at 21 residue positions (black crosses)

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

DOI no: 10.1002/hep.26685

Hepatology 59:408-422 (2014)

PubMed id: 24022996

Structure-guided design affirms inhibitors of hepatitis C virus p7 as a viable class of antivirals targeting virion release.

T.L.Foster, G.S.Thompson, A.P.Kalverda, J.Kankanala, M.Bentham, L.F.Wetherill, J.Thompson, A.M.Barker, D.Clarke, M.Noerenberg, A.R.Pearson, D.J.Rowlands, S.W.Homans, M.Harris, R.Foster, S.Griffin.

ABSTRACT

Current interferon-based therapy for hepatitis C virus (HCV) infection is inadequate, prompting a shift toward combinations of direct-acting antivirals (DAA) with the first protease-targeted drugs licensed in 2012. Many compounds are in the pipeline yet primarily target only three viral proteins, namely, NS3/4A protease, NS5B polymerase, and NS5A. With concerns growing over resistance, broadening the repertoire for DAA targets is a major priority. Here we describe the complete structure of the HCV p7 protein as a monomeric hairpin, solved using a novel combination of chemical shift and nuclear Overhauser effect (NOE)-based methods. This represents atomic resolution information for a full-length virus-coded ion channel, or "viroporin," whose essential functions represent a clinically proven class of antiviral target exploited previously for influenza A virus therapy. Specific drug-protein interactions validate an allosteric site on the channel periphery and its relevance is demonstrated by the selection of novel, structurally diverse inhibitory small molecules with nanomolar potency in culture. Hit compounds represent a 10,000-fold improvement over prototypes, suppress rimantadine resistance polymorphisms at submicromolar concentrations, and show activity against other HCV genotypes. Conclusion: This proof-of-principle that structure-guided design can lead to drug-like molecules affirms p7 as a much-needed new target in the burgeoning era of HCV DAA. (Hepatology 2014;59:408-422).