Dynamics study on the anti-human immunodeficiency virus chemokine viral macrophage-inflammatory protein-II (VMIP-II) reveals a fully monomeric protein

Encoded by Kaposi's sarcoma-associated herpesvirus, viral macrophage-inflam matory protein-II (VMIP-II) is unique among CC chemokines in that it has be en shown to bind to the CXC chemokine receptor CXCR4 as well as to a variet y of CC chemokine receptors. This unique binding ability allows vMIP-II to block infection by a wide range of human immunodeficiency virus type I (HIV -1) strains, but the structural and dynamic basis for this broad range of b inding is not known. N-15 T-1, T-2 and N-15{-H-N} nuclear Overhauser effect (NOE) values of vMIP-II, determined through a series of heteronuclear mult idimensional nuclear magnetic resonance (NMR) experiments, were used to obt ain information about the backbone dynamics of the protein. Whereas almost all chemokine structures reveal a dimer or multimer, vMIP-II has a rotation al correlation time (tau(c)) of 4.7 +/- 0.3 ns, which is consistent with a monomeric chemokine. The rotational diffusion anisotropy, D-parallel to/D-p erpendicular to, is approximately 1.5 +/- 0.1. The conformation of vMIP-II is quite similar to other known chemokines, containing an unstructured N-te rminus followed by an ordered turn, three beta-strands arranged in an antip arallel fashion, and one C-terminal alpha-helix that lies across the beta-s trands. Most of the protein is well-ordered on a picosecond time scale, wit h an average order parameter S-2 (excluding the N-terminal 13 amino acids) of 0.83 +/- 0.09, and with even greater order in regions of secondary struc ture. The NMR data reveal that the N-terminus, which in other chemokines ha s been implicated in receptor binding, extends like a flexible tail in solu tion and possesses no secondary structure. The region of the ordered turn, including residues 25-28, experiences conformational exchange dynamics. The implications of these NMR data to the broad receptor binding capability of vMIP-II. are discussed.