A hallmark of chronic inflammatory diseases is the excessive accumulation of white blood cells in the affected tissues, which is coordinated by pro-inflammatory mediators called chemokines. Humans have ~50 chemokines divided into two major classes – CC and CXC chemokines. Specific groups of chemokines are associated with different inflammatory diseases; for example, the chemokines CCL2, CCL7 and CCL8 are involved in atherosclerosis. As natural chemokine inhibitors, evasin proteins secreted in tick saliva are potential anti-inflammatory therapeutic agents. However, the development of tick evasins as chemokine-targeted anti-inflammatory therapeutics requires an understanding of the factors controlling their chemokine-binding specificity. Structures of the evasins EVA-P974 and EVA-AAM02 bound to several human CC chemokine ligands (CCL7, CCL11, CCL16 and CCL17) and to a CCL8-CCL7 chimera reveal that the specificity of evasins for chemokines of the CC subfamily is defined by conserved, rigid backbone-backbone interactions. Whereas the preference for a subset of CC chemokines is controlled by side chain interactions at hotspots in flexible structural elements. The substitution of amino acid residues at hotspots provides evasin variants with new chemokine-binding properties. The structures of engineered evasins bound to several chemokines reveal an underlying molecular mechanism. This molecular understanding enabled us to rationally engineer evasins with modified chemokine selectivity, providing a foundation for the future engineering of evasins as anti-inflammatory therapeutics.
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