Molecular determinants for CC-chemokine recognition by a poxvirus CC-chemokine inhibitor

doi:10.1073/pnas.171069398

Molecular determinants for CC-chemokine recognition by a poxvirus CC-chemokine inhibitor

^*Viral Immunology & Pathogenesis Laboratories, John P. Robarts Research Institute, 1400 Western Road, Room 133, London, ON, Canada N6G 2V4; ^†Department of Microbiology and Immunology, University of Western Ontario, London, ON, Canada N6A 5C1; and ^‡Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720

Edited by Bernard Moss, National Institutes of Health, Bethesda, MD, and approved June 15, 2001 (received for review February 11, 2001)

Abstract

Poxviruses express a family of secreted proteins that bind with high affinity to chemokines and antagonize the interaction with their cognate G protein-coupled receptors (GPCRs). These viral inhibitors are novel in structure and, unlike cellular chemokine receptors, are able to specifically interact with most, if not all, CC-chemokines. We therefore sought to define the structural features of CC-chemokines that facilitate this broad-spectrum interaction. Here, we identify the residues present on human monocyte chemoattractant protein-1 (MCP-1) that are required for high-affinity interaction with the vaccinia virus 35-kDa CC-chemokine binding protein (VV-35kDa). Not only do these residues correspond to those required for interaction with the cognate receptor CCR2b but they are also conserved among many CC-chemokines. Thus, the results provide a structural basis for the ability of VV-35kDa to promiscuously recognize CC-chemokines and block binding to their receptors.

Footnotes

↵ § To whom reprint requests should be addressed. E-mail: mcfadden{at}rri.on.ca.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

CBP,

chemokine binding protein;

CPV,

cowpox virus;

GPCR,

G protein-coupled receptor;

MCP-1,

monocyte chemoattractant protein-1;

RU,

response units;

VV-35kDa,

vaccinia virus 35-kDa protein;

SPR,

surface plasmon resonance;

wt,

wild type;

MIP-1α,

macrophage inflammatory protein-1α