M. Samson et al., THE 2ND EXTRACELLULAR LOOP OF CCR5 IS THE MAJOR DETERMINANT OF LIGANDSPECIFICITY, The Journal of biological chemistry, 272(40), 1997, pp. 24934-24941
The chemokine receptor CCR5 binds macrophage inflammatory protein (MIP
)-1 alpha, MIP-1 beta, and regulated on activation, normal T-cell expr
essed and secreted (RANTES), and constitutes the major co-receptor all
owing infection of CD4(+) T lymphocytes, macrophages, and microglial c
ells by macrophage-tropic strains of human and simian immunodeficiency
virus, CCR5 is most closely related to CCR2b, another chemokine recep
tor that responds to monocyte chemoattractant protein (MCP)-1, MCP-2,
MCP-3, and MCP-4, We have investigated by mutagenesis the regions of C
CR5 and CCR2b involved in the specificity of binding and functional re
sponse to their respective ligands, We demonstrate that the key region
of CCR5 involved in its specific interaction with MIP-1 alpha, MIP-1
beta, and RANTES, and its subsequent activation, lies within the secon
d extracellular loop (and possibly the adjacent transmembrane segments
), Conversely, the NH2-terminal domain of CCR2b is responsible for the
high affinity binding of MCP-1, but is not sufficient to confer activ
ation of the intracellular cascades. Extracellular loops of the recept
or, among which the second loop plays a prominent role, are necessary
to achieve efficient signaling of the receptor, These data complement
our previous mapping of CCR5 domains functionally involved in the fusi
on process with the human immunodeficiency virus envelope, and will he
lp in the development of agents able to interfere with the early steps
of viral infection.