The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20071677
The Journal of Experimental Medicine, Vol. 204, No. 13, 3157-3172
The Rockefeller University Press, 0022-1007 $30.00
© Alexander-Brett et al.
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ARTICLE

 Dual GPCR and GAG mimicry by the M3 chemokine decoy receptor

Jennifer M. Alexander-Brett1,2 and Daved H. Fremont1,2,3

1 Department of Pathology and Immunology, 2 Molecular Biophysics and Medical Scientist Training Program, and 3 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110

CORRESPONDENCE D.H. Fremont: fremont{at}pathology.wustl.edu

Viruses have evolved a myriad of evasion strategies focused on undermining chemokine-mediated immune surveillance, exemplified by the mouse {gamma}-herpesvirus 68 M3 decoy receptor. Crystal structures of M3 in complex with C chemokine ligand 1/lymphotactin and CC chemokine ligand 2/monocyte chemoattractant protein 1 reveal that invariant chemokine features associated with G protein–coupled receptor binding are primarily recognized by the decoy C-terminal domain, whereas the N-terminal domain (NTD) reconfigures to engage divergent basic residue clusters on the surface of chemokines. Favorable electrostatic forces dramatically enhance the association kinetics of chemokine binding by M3, with a primary role ascribed to acidic NTD regions that effectively mimic glycosaminoglycan interactions. Thus, M3 employs two distinct mechanisms of chemical imitation to potently sequester chemokines, thereby inhibiting chemokine receptor binding events as well as the formation of chemotactic gradients necessary for directed leukocyte trafficking.

Abbreviations used: BSA, buried surface area; CCL, CC chemokine ligand; CHO, Chinese hamster ovary; CTD, C-terminal domain; CXCL, CXC chemokine ligand; FGFR, fibroblast growth factor receptor; GAG, glycosaminoglycan; GPCR, G protein–coupled receptor; IP, IFN-inducible protein; KD, dissociation constant; KI, inhibition dissociation constant; MHV68, mouse {gamma}-herpesvirus 68; MIP, macrophage inflammatory protein; NTD, N-terminal domain; pI, isoelectric point; RMSD, root mean square deviation; SPR, surface plasmon resonance; VEGF, vascular endothelial growth factor; XCL, C chemokine ligand.


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