This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arnold, P. L. Articles by Fremont, D. H. Search for Related Content PubMed PubMed Citation Articles by Arnold, P. L. Articles by Fremont, D. H.

 Previous Article  |  Next Article 

Journal of Virology, August 2006, p. 7439-7449, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00576-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Structural Determinants of Chemokine Binding by an Ectromelia Virus-Encoded Decoy Receptor

Department of Pathology and Immunology,¹ Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110-1093²

Received 20 March 2006/ Accepted 15 May 2006

The EVM1 protein encoded by Ectromelia virus is a member of a highly conserved family of poxvirus chemokine binding proteins that interfere with host immune surveillance processes. EVM1 is abundantly expressed early during mousepox infection and is able to selectively bind CC chemokines and inhibit their interactions with host receptors. Here, we characterize the interaction between EVM1 and the human and murine chemokines CCL3 (MIP-1), CCL2 (MCP-1), and CCL5 (RANTES). Each of these CC chemokines binds EVM1 with 1:1 stoichiometry and equilibrium dissociation constants ranging from 29 pM to 20 nM. The interactions are characterized by rapid-association kinetics between acidic EVM1 and generally basic chemokines with half-lives enduring up to 30 min. The 2.6-Å crystal structure of EVM1 reveals a globular ß sandwich with a large, sequence-conserved surface patch encircled by acidic residues on one face of the protein. To determine whether this conserved cluster of residues is involved in chemokine engagement, a structure-based mutational analysis of EVM1 was employed. Mapping of the mutational results onto the surface of EVM1 reveals that a cluster of five residues (I173, S171, S134, N136, and Y69) emanating from one ß sheet is critical for CCL2 and CCL3 sequestration. Additionally, we find that the extended ß2-ß4 loop flanking this conserved cluster is also essential for high-affinity, lasting interactions with chemokines. This analysis provides insight into the mechanism of CC-chemokine inhibition employed by the poxvirus family of chemokine decoy receptors.

This article has been cited by other articles:

• Ruiz-Arguello, M. B., Smith, V. P., Campanella, G. S. V., Baleux, F., Arenzana-Seisdedos, F., Luster, A. D., Alcami, A. (2008). An Ectromelia Virus Protein That Interacts with Chemokines through Their Glycosaminoglycan Binding Domain. J. Virol. 82: 917-926 [Abstract] [Full Text]  
• Alexander-Brett, J. M., Fremont, D. H. (2007). Dual GPCR and GAG mimicry by the M3 chemokine decoy receptor. J. Exp. Med. 204: 3157-3172 [Abstract] [Full Text]