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Encoded by Kaposi's sarcoma-associated herpesvirus, viral macrophage-inflammatory protein-II (VMIP-II) is unique among CC chemokines in that it has been shown to bind to the CXC chemokine receptor CXCR4 as well as to a variety 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 binding is not known. 15N T1, T2 and 15N[-HN] nuclear Overhauser effect (NOE) values of vMIP-II, determined through a series of heteronuclear multidimensional nuclear magnetic resonance (NMR) experiments, were used to obtain information about the backbone dynamics of the protein. Whereas almost all chemokine structures reveal a dimer or multimer, vMIP-II has a rotational correlation time (tauc) of 4.7 +/- 0.3 ns, which is consistent with a monomeric chemokine. The rotational diffusion anisotropy, D parallel/D perpendicular, is approximately 1.5 +/- 0.1. The conformation of vMIP-II is quite similar to other known chemokines, containing an unstructured N-terminus followed by an ordered turn, three beta-strands arranged in an antiparallel fashion, and one C-terminal alpha-helix that lies across the beta-strands. Most of the protein is well-ordered on a picosecond time scale, with an average order parameter S2 (excluding the N-terminal 13 amino acids) of 0.83 +/- 0. 09, and with even greater order in regions of secondary structure. The NMR data reveal that the N-terminus, which in other chemokines has been implicated in receptor binding, extends like a flexible tail in solution 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.