HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 28, 20584-20592, July 13, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/28/20584    most recent M611619200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yin, C. Articles by Montelione, G. T. Search for Related Content PubMed PubMed Citation Articles by Yin, C. Articles by Montelione, G. T. Social Bookmarking                      What's this?

Conserved Surface Features Form the Double-stranded RNA Binding Site of Non-structural Protein 1 (NS1) from Influenza A and B Viruses^*

Cuifeng Yin¹, Javed A. Khan¹, G. V. T. Swapna, Asli Ertekin², Robert M. Krug^¶3, Liang Tong⁴, and Gaetano T. Montelione⁵

From the Center for Advanced Biotechnology and Medicine, Northeast Structural Genomics Consortium, Department of Molecular Biology and Biochemistry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854, Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, New York, New York 10027, and ^¶Section of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas 78712

Influenza A viruses cause a highly contagious respiratory disease in humans and are responsible for periodic widespread epidemics with high mortality rates. The influenza A virus NS1 protein (NS1A) plays a key role in countering host antiviral defense and in virulence. The 73-residue N-terminal domain of NS1A (NS1A-(1–73)) forms a symmetric homodimer with a unique six-helical chain fold. It binds canonical A-form double-stranded RNA (dsRNA). Mutational inactivation of this dsRNA binding activity of NS1A highly attenuates virus replication. Here, we have characterized the unique structural features of the dsRNA binding surface of NS1A-(1–73) using NMR methods and describe the 2.1-Å x-ray crystal structure of the corresponding dsRNA binding domain from human influenza B virus NS1B-(15–93). These results identify conserved dsRNA binding surfaces on both NS1A-(1–73) and NS1B-(15–93) that are very different from those indicated in earlier "working models" of the complex between dsRNA and NS1A-(1–73). The combined NMR and crystallographic data reveal highly conserved surface tracks of basic and hydrophilic residues that interact with dsRNA. These tracks are structurally complementary to the polyphosphate backbone conformation of A-form dsRNA and run at an 45° angle relative to the axes of helices 2/2'. At the center of this dsRNA binding epitope, and common to NS1 proteins from influenza A and B viruses, is a deep pocket that includes both hydrophilic and hydrophobic amino acids. This pocket provides a target on the surface of the NS1 protein that is potentially suitable for the development of antiviral drugs targeting both influenza A and B viruses.

Received for publication, December 19, 2006 , and in revised form, April 30, 2007.

The atomic coordinates and structure factors (code 1xeq) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Protein Structure Initiative Grants U54 GM074958 (to G. T. M.), AI49475 (to L. T.), and AI11772 (to R. M. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5 and Table S-I.

¹ These authors contributed equally to this work.

² A graduate fellow of the Biological, Mathematical, and Physical Sciences (BioMAPS) program at Rutgers University.

³ To whom correspondence may be addressed. E-mail: rkrug{at}mail.utexas.edu. ⁴ To whom correspondence may be addressed. E-mail: ltong{at}columbia.edu. ⁵ To whom correspondence may be addressed. E-mail: guy{at}cabm.rutgers.edu.

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

This article has been cited by other articles:

				R.-L. Kuo and R. M. Krug Influenza A Virus Polymerase Is an Integral Component of the CPSF30-NS1A Protein Complex in Infected Cells J. Virol., February 15, 2009; 83(4): 1611 - 1616. [Abstract] [Full Text] [PDF]

				J. Schneider, B. Dauber, K. Melen, I. Julkunen, and T. Wolff Analysis of Influenza B Virus NS1 Protein Trafficking Reveals a Novel Interaction with Nuclear Speckle Domains J. Virol., January 15, 2009; 83(2): 701 - 711. [Abstract] [Full Text] [PDF]

				D. W. Leung, N. D. Ginder, D. B. Fulton, J. Nix, C. F. Basler, R. B. Honzatko, and G. K. Amarasinghe Structure of the Ebola VP35 interferon inhibitory domain PNAS, January 13, 2009; 106(2): 411 - 416. [Abstract] [Full Text] [PDF]

				B. G. Hale, R. E. Randall, J. Ortin, and D. Jackson The multifunctional NS1 protein of influenza A viruses J. Gen. Virol., October 1, 2008; 89(10): 2359 - 2376. [Abstract] [Full Text] [PDF]

				K. Das, L.-C. Ma, R. Xiao, B. Radvansky, J. Aramini, L. Zhao, J. Marklund, R.-L. Kuo, K. Y. Twu, E. Arnold, et al. Structural basis for suppression of a host antiviral response by influenza A virus PNAS, September 2, 2008; 105(35): 13093 - 13098. [Abstract] [Full Text] [PDF]

				Y.-G. Chang, X.-Z. Yan, Y.-Y. Xie, X.-C. Gao, A.-X. Song, D.-E. Zhang, and H.-Y. Hu Different Roles for Two Ubiquitin-like Domains of ISG15 in Protein Modification J. Biol. Chem., May 9, 2008; 283(19): 13370 - 13377. [Abstract] [Full Text] [PDF]