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

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