CCR2 and CCR5 receptor-binding properties of herpesvirus-8 vMIP-II based on sequence analysis and its solution structure

Human herpesvirus-8 (HHV-8) is the infectious agent responsible for Kaposi' s sarcoma and encodes a protein, macrophage inflammatory protein-II (vMIP-I I), which shows sequence similarity to the human CC chemokines. vMIP-II has broad receptor specificity that crosses chemokine receptor subfamilies, an d inhibits HIV-1 viral entry mediated by numerous chemokine receptors. In t his study, the solution structure of chemically synthesized vMIP-II was det ermined by nuclear magnetic resonance. The protein is a monomer and possess es the chemokine fold consisting of a flexible N-terminus, three antiparall el beta strands, and a C-terminal alpha helix. Except for the N-terminal re sidues (residues 1-13) and the last two C-terminal residues (residues 73-74 ), the structure of vMIP-II is well-defined, exhibiting average rmsd of 0.3 5 and 0.90 Angstrom for the backbone heavy atoms and all heavy atoms of res idues 14-72, respectively. Taking into account the sequence differences bet ween the various CC chemokines and comparing their three-dimensional struct ures allows us to implicate residues that influence the quaternary structur e and receptor binding and activation of these proteins in solution. The an alysis of the sequence and three-dimensional structure of vMIP-II indicates the presence of epitopes involved in binding two receptors CCR2 and CCR5. We propose that vMIP-II was initially specific for CCR5 and acquired recept or-binding properties to CCR2 and other chemokine receptors.