PDBsum entry 2m6x

Membrane protein

PDB id: 2m6x

Contents

Protein chains

(+ 0 more) 63 a.a.

PDB id:

2m6x

Name:

Membrane protein

Title:

Structure of the p7 channel of hepatitis c virus, genotype 5a

Structure:

P7. Chain: a, b, c, d, e, f. Engineered: yes. Mutation: yes

Source:

Hepatitis c virus. Hcv. Organism_taxid: 356419. Strain: euh1480. Variant: genotype 5a. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

15 models

Authors:

B.Ouyang,J.J.Chou

Key ref:

B.OuYang et al. (2013). Unusual architecture of the p7 channel from hepatitis C virus. Nature, 498, 521-525. PubMed id: 23739335 DOI: 10.1038/nature12283

Date:

12-Apr-13 Release date: 12-Jun-13

Protein chains

O39928  (POLG_HCVEV) -  Genome polyprotein from Hepatitis C virus genotype 5a (isolate EUH1480)

Seq: 3014 a.a.

Struc: 63 a.a.*

* PDB and UniProt seqs differ at 5 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: 10.1038/nature12283

Nature 498:521-525 (2013)

PubMed id: 23739335

Unusual architecture of the p7 channel from hepatitis C virus.

B.OuYang, S.Xie, M.J.Berardi, X.Zhao, J.Dev, W.Yu, B.Sun, J.J.Chou.

ABSTRACT

The hepatitis C virus (HCV) has developed a small membrane protein, p7, which remarkably can self-assemble into a large channel complex that selectively conducts cations. We wanted to examine the structural solution that the viroporin adopts in order to achieve selective cation conduction, because p7 has no homology with any of the known prokaryotic or eukaryotic channel proteins. The activity of p7 can be inhibited by amantadine and rimantadine, which are potent blockers of the influenza M2 channel and licensed drugs against influenza infections. The adamantane derivatives have been used in HCV clinical trials, but large variation in drug efficacy among the various HCV genotypes has been difficult to explain without detailed molecular structures. Here we determine the structures of this HCV viroporin as well as its drug-binding site using the latest nuclear magnetic resonance (NMR) technologies. The structure exhibits an unusual mode of hexameric assembly, where the individual p7 monomers, i, not only interact with their immediate neighbours, but also reach farther to associate with the i+2 and i+3 monomers, forming a sophisticated, funnel-like architecture. The structure also points to a mechanism of cation selection: an asparagine/histidine ring that constricts the narrow end of the funnel serves as a broad cation selectivity filter, whereas an arginine/lysine ring that defines the wide end of the funnel may selectively allow cation diffusion into the channel. Our functional investigation using whole-cell channel recording shows that these residues are critical for channel activity. NMR measurements of the channel-drug complex revealed six equivalent hydrophobic pockets between the peripheral and pore-forming helices to which amantadine or rimantadine binds, and compound binding specifically to this position may allosterically inhibit cation conduction by preventing the channel from opening. Our data provide a molecular explanation for p7-mediated cation conductance and its inhibition by adamantane derivatives.