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Journal of Virology, July 2009, p. 6534-6545, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00189-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Crystal Structures of Chikungunya and Venezuelan Equine Encephalitis Virus nsP3 Macro Domains Define a Conserved Adenosine Binding Pocket {triangledown}

Hélène Malet,1,{dagger} Bruno Coutard,1 Saïd Jamal,1 Hélène Dutartre,1,{ddagger} Nicolas Papageorgiou,1 Maarit Neuvonen,2 Tero Ahola,2 Naomi Forrester,3,§ Ernest A. Gould,3 Daniel Lafitte,4 Francois Ferron,1 Julien Lescar,1 Alexander E. Gorbalenya,5 Xavier de Lamballerie,6 and Bruno Canard1*

Architecture et Fonction des Macromolécules Biologiques, CNRS and Universités d'Aix-Marseille I et II, UMR 6098, ESIL Case 925, 13288 Marseille, France,1 Institute of Biotechnology, University of Helsinki, P.O. Box 56, Viikinkaari 9, 00014 Helsinki, Finland,2 CEH Oxford, Mansfield Road, Oxford OX1 3SR, United Kingdom,3 Marseille Protéomique, INSERM UMR 911 CRO2, Aix-Marseille Université, Faculté de Pharmacie, 27 Bd. Jean Moulin, 13285 Marseille cedex 05, France,4 Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands,5 UMR190, Emergence des Pathologies Virales, Institut de Recherche pour le Développement—Université de la Méditerranée, Faculté de Médecine de Marseille, 27 Bd. Jean Moulin, 13005 Marseille cedex 05, France6

Received 27 January 2009/ Accepted 14 April 2009

Macro domains (also called "X domains") constitute a protein module family present in all kingdoms of life, including viruses of the Coronaviridae and Togaviridae families. Crystal structures of the macro domain from the Chikungunya virus (an "Old World" alphavirus) and the Venezuelan equine encephalitis virus (a "New World" alphavirus) were determined at resolutions of 1.65 and 2.30 Å, respectively. These domains are active as adenosine di-phosphoribose 1''-phosphate phosphatases. Both the Chikungunya and the Venezuelan equine encephalitis virus macro domains are ADP-ribose binding modules, as revealed by structural and functional analysis. A single aspartic acid conserved through all macro domains is responsible for the specific binding of the adenine base. Sequence-unspecific binding to long, negatively charged polymers such as poly(ADP-ribose), DNA, and RNA is observed and attributed to positively charged patches outside of the active site pocket, as judged by mutagenesis and binding studies. The crystal structure of the Chikungunya virus macro domain with an RNA trimer shows a binding mode utilizing the same adenine-binding pocket as ADP-ribose, but avoiding the ADP-ribose 1''-phosphate phosphatase active site. This leaves the AMP binding site as the sole common feature in all macro domains.

* Corresponding author. Mailing address: Architecture et Fonction des Macromolécules Biologiques, CNRS and Universités d'Aix-Marseille I et II, UMR 6098, ESIL Case 925, 13288 Marseille, France. Phone: 33 491 82 86 44. Fax: 33 491 82 86 46. E-mail: bruno.canard{at}afmb.univ-mrs.fr

{triangledown} Published ahead of print on 22 April 2009.

{dagger} Present address: School of Crystallography, Birkbeck College, University of London, Malet St., London WC1E 7HX, United Kingdom.

{ddagger} Present address: Baylor Institute for Immunological Research, INSERM U899, 3434 Live Oak St., Dallas, TX 75204.

§ Present address: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77551.

Journal of Virology, July 2009, p. 6534-6545, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00189-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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