3ZD0
The Solution Structure of Monomeric Hepatitis C Virus p7 Yields Potent Inhibitors of Virion Release
Summary for 3ZD0
| Entry DOI | 10.2210/pdb3zd0/pdb |
| NMR Information | BMRB: 18863 |
| Descriptor | P7 PROTEIN (1 entity in total) |
| Functional Keywords | transport protein, antiviral, ion channel, viroporin |
| Biological source | HEPATITIS C VIRUS (HCV) |
| Total number of polymer chains | 1 |
| Total formula weight | 9065.47 |
| Authors | Foster, T.L.,Sthompson, G.,Kalverda, A.P.,Kankanala, J.,Thompson, J.,Barker, A.M.,Clarke, D.,Noerenberg, M.,Pearson, A.R.,Rowlands, D.J.,Homans, S.W.,Harris, M.,Foster, R.,Griffin, S.D.C. (deposition date: 2012-11-23, release date: 2013-09-04, Last modification date: 2024-06-19) |
| Primary citation | Foster, T.L.,Thompson, G.S.,Kalverda, A.P.,Kankanala, J.,Bentham, M.,Wetherill, L.F.,Thompson, J.,Barker, A.M.,Clarke, D.,Noerenberg, M.,Pearson, A.R.,Rowlands, D.J.,Homans, S.W.,Harris, M.,Foster, R.,Griffin, S.D.C. Structure-Guided Design Affirms Inhibitors of Hepatitis C Virus P7 as a Viable Class of Antivirals Targeting Virion Release Hepatology, 59:408-, 2014 Cited by PubMed 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. PubMed: 24022996DOI: 10.1002/HEP.26685 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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