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. 2006 Sep 19;103(38):13985-90.
doi: 10.1073/pnas.0602142103. Epub 2006 Sep 8.

Solution structure of the complex between poxvirus-encoded CC chemokine inhibitor vCCI and human MIP-1beta

Li Zhang  1 , Michele Derider, Melissa A McCornack, Shu-Chuan Jao, Nancy Isern, Traci Ness, Richard Moyer, Patricia J LiWang
Affiliations

Solution structure of the complex between poxvirus-encoded CC chemokine inhibitor vCCI and human MIP-1beta

Li Zhang et al. Proc Natl Acad Sci U S A. .

Abstract

Chemokines (chemotactic cytokines) comprise a large family of proteins that recruit and activate leukocytes, giving chemokines a major role in both immune response and inflammation-related diseases. The poxvirus-encoded viral CC chemokine inhibitor (vCCI) binds to many CC chemokines with high affinity, acting as a potent inhibitor of chemokine action. We have used heteronuclear multidimensional NMR to determine the structure of an orthopoxvirus vCCI in complex with a human CC chemokine, MIP-1beta (macrophage inflammatory protein 1beta). vCCI binds to the chemokine with 1:1 stoichiometry, forming a complex of 311 aa. vCCI uses residues from its beta-sheet II to interact with a surface of MIP-1beta that includes residues adjacent to its N terminus, as well as residues in the 20's region and the 40's loop. This structure reveals the strategy used by vCCI to tightly bind numerous chemokines while retaining selectivity for the CC chemokine subfamily.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Sequence alignment of five members of the orthopox vCCI family. Alignments were made by using ClustalW. RPV, rabbitpox virus; VAR, variola virus; VVL, vaccinia virus Lister strain; VVC, vaccinia virus Copenhagen strain; CPV, cowpox virus. Conserved residues are highlighted in yellow.
Fig. 2.
Fig. 2.
Observation of vCCI:MIP-1β interaction. (A) Overlay of the 15N heteronuclear single quantum correlation (HSQC) spectra of free (black) and liganded (red) vCCI. (B) Chemical shift perturbation mapping of vCCI upon addition of MIP-1β. Residues with weighted average HN and N chemical shift perturbation >1 standard deviation (SD) from the mean value are shown in red. Residues that are missing from the HSQC because of chemical exchange line broadening are shown in yellow. (C) Overlay of the 15N HSQC spectra of free (black) and liganded (red) MIP-1β.
Fig. 3.
Fig. 3.
Solution structure of the vCCI:MIP-1β complex. Superposition of 15 NMR structures is shown, with the vCCI backbone colored red and selected side chains colored pink. The MIP-1β backbone is blue, and selected side chains are shown in green.
Fig. 4.
Fig. 4.
Detailed views of the VCCI:MIP–1β interaction. (A) MIP-1β Phe-13 (green) and the surrounding hydrophobic residues (yellow) from vCCI. (B) View of the 20′s region and the 40′s loop of MIP-1β (green) in proximity to vCCI acidic residues (red). In the present structure, MIP-1β residues 45, 46, and 48 are changed to Ala to enhance solubility.
Fig. 5.
Fig. 5.
Sequence alignment of human CC chemokines with high affinity to vCCI. Conserved cysteine residues are highlighted in yellow. Positions highlighted with red indicate residues that likely confer high-affinity binding to vCCI. The numbering is according to the MIP-1β sequence.
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