Advertisement
JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

A more recent version of this article appeared on August 19, 2005
This Article
Right arrow Full Text (Accepted Manuscript)
Right arrow Supplemental Data
Right arrow All Versions of this Article:
280/33/29765    most recent
M505423200v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Di Marco, S.
Right arrow Articles by Carfi, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Di Marco, S.
Right arrow Articles by Carfi, A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Papers In Press, published online ahead of print June 13, 2005
J. Biol. Chem, 10.1074/jbc.M505423200
Submitted on May 17, 2005
Accepted on June 13, 2005

Interdomain communication in hepatitis C virus polymerase abolished by small-molecule inhibitors bound to a novel allosteric site

Stefania Di Marco, Cinzia Volpari, Licia Tomei, Sergio Altamura, Steven Harper, Frank Narjes, Uwe Koch, Michael Rowley, Raffaele De Francesco, Giovanni Migliaccio, and Andrea Carfi

Department of Biochemistry, IRBM P.Angeletti, Pomezia, Rome I-00040

Corresponding Author: andrea_carfi{at}merck.com

The hepatitis C virus (HCV) polymerase is required for replication of the viral genome and is a key target for therapeutic intervention against HCV. We have determined the crystal structures of the HCV polymerase complexed with two indole-based allosteric inhibitors at 2.3 Å and 2.4 Å resolution. The structures show that these inhibitors bind to a site on the surface of the thumb domain. A cyclohexyl and phenyl ring substituents, bridged by an indole moiety, fill two closely spaced pockets whereas a carboxylate substituent forms a salt bridge with an exposed arginine side chain. Interestingly, in the apoenzyme, the inhibitor binding site is occupied by a small alpha-helix at the tip of the N-terminal loop that connects fingers and thumb domains. Thus, these molecules inhibit the enzyme by preventing formation of intramolecular contacts between these two domains and consequently precluding their coordinated movements during RNA synthesis. Our structures identify a novel mechanism by which a new class of allosteric inhibitors inhibits the HCV polymerase and open the way to the development of novel antiviral agents against this clinically relevant human pathogen.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Antimicrob. Agents Chemother.Home page
O. Nyanguile, F. Pauwels, W. Van den Broeck, C. W. Boutton, L. Quirynen, T. Ivens, L. van der Helm, G. Vandercruyssen, W. Mostmans, F. Delouvroy, et al.
1,5-Benzodiazepines, a Novel Class of Hepatitis C Virus Polymerase Nonnucleoside Inhibitors
Antimicrob. Agents Chemother., December 1, 2008; 52(12): 4420 - 4431.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
K. J. Herlihy, J. P. Graham, R. Kumpf, A. K. Patick, R. Duggal, and S. T. Shi
Development of Intergenotypic Chimeric Replicons To Determine the Broad-Spectrum Antiviral Activities of Hepatitis C Virus Polymerase Inhibitors
Antimicrob. Agents Chemother., October 1, 2008; 52(10): 3523 - 3531.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Nikonov, E. Juronen, and M. Ustav
Functional Characterization of Fingers Subdomain-specific Monoclonal Antibodies Inhibiting the Hepatitis C Virus RNA-dependent RNA Polymerase
J. Biol. Chem., August 29, 2008; 283(35): 24089 - 24102.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Chinnaswamy, I. Yarbrough, S. Palaninathan, C. T. R. Kumar, V. Vijayaraghavan, B. Demeler, S. M. Lemon, J. C. Sacchettini, and C. C. Kao
A Locking Mechanism Regulates RNA Synthesis and Host Protein Interaction by the Hepatitis C Virus Polymerase
J. Biol. Chem., July 18, 2008; 283(29): 20535 - 20546.
[Abstract] [Full Text] [PDF]

Home page
 J Antimicrob ChemotherHome page
S. Le Pogam, A. Seshaadri, A. Kosaka, S. Chiu, H. Kang, S. Hu, S. Rajyaguru, J. Symons, N. Cammack, and I. Najera
Existence of hepatitis C virus NS5B variants naturally resistant to non-nucleoside, but not to nucleoside, polymerase inhibitors among untreated patients
J. Antimicrob. Chemother., June 1, 2008; 61(6): 1205 - 1216.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
J. Deval, M. H. Powdrill, C. M. D'Abramo, L. Cellai, and M. Gotte
Pyrophosphorolytic Excision of Nonobligate Chain Terminators by Hepatitis C Virus NS5B Polymerase
Antimicrob. Agents Chemother., August 1, 2007; 51(8): 2920 - 2928.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
F. Pauwels, W. Mostmans, L. M. M. Quirynen, L. van der Helm, C. W. Boutton, A.-S. Rueff, E. Cleiren, P. Raboisson, D. Surleraux, O. Nyanguile, et al.
Binding-Site Identification and Genotypic Profiling of Hepatitis C Virus Polymerase Inhibitors
J. Virol., July 1, 2007; 81(13): 6909 - 6919.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Deval, C. M. D'Abramo, Z. Zhao, S. McCormick, D. Coutsinos, S. Hess, M. Kvaratskhelia, and M. Gotte
High Resolution Footprinting of the Hepatitis C Virus Polymerase NS5B in Complex with RNA
J. Biol. Chem., June 8, 2007; 282(23): 16907 - 16916.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
J. M. Robida, H. B. Nelson, Z. Liu, and H. Tang
Characterization of Hepatitis C Virus Subgenomic Replicon Resistance to Cyclosporine In Vitro
J. Virol., June 1, 2007; 81(11): 5829 - 5840.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
W. Yang, Y. Sun, A. Phadke, M. Deshpande, and M. Huang
Hepatitis C Virus (HCV) NS5B Nonnucleoside Inhibitors Specifically Block Single-Stranded Viral RNA Synthesis Catalyzed by HCV Replication Complexes In Vitro
Antimicrob. Agents Chemother., January 1, 2007; 51(1): 338 - 342.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
S. Le Pogam, H. Kang, S. F. Harris, V. Leveque, A. M. Giannetti, S. Ali, W.-R. Jiang, S. Rajyaguru, G. Tavares, C. Oshiro, et al.
Selection and Characterization of Replicon Variants Dually Resistant to Thumb- and Palm-Binding Nonnucleoside Polymerase Inhibitors of the Hepatitis C Virus.
J. Virol., June 1, 2006; 80(12): 6146 - 6154.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
R. W. Mahley, K. H. Weisgraber, and Y. Huang
Inaugural Article: Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer's disease
PNAS, April 11, 2006; 103(15): 5644 - 5651.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. Kukolj, G. A. McGibbon, G. McKercher, M. Marquis, S. Lefebvre, L. Thauvette, J. Gauthier, S. Goulet, M.-A. Poupart, and P. L. Beaulieu
Binding Site Characterization and Resistance to a Class of Non-nucleoside Inhibitors of the Hepatitis C Virus NS5B Polymerase
J. Biol. Chem., November 25, 2005; 280(47): 39260 - 39267.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
Advertisement
spacer
Advertisement
Advertisement