6I31

Crystal structure of the tick chemokine-binding protein Evasin-3

Summary for 6I31

• Entry DOI: 10.2210/pdb6i31/pdb
• Descriptor: Evasin-3, CADMIUM ION (3 entities in total)
• Functional Keywords: chemokine-binding tick evasin saliva, peptide binding protein
• Biological source: Rhipicephalus sanguineus (Brown dog tick)
• Total number of polymer chains: 2
• Total formula weight: 14138.13

Authors

Dias, J.M.,Shaw, J.P. (deposition date: 2018-11-02, release date: 2019-06-19, Last modification date: 2024-11-20)

Primary citation

Lee, A.W.,Deruaz, M.,Lynch, C.,Davies, G.,Singh, K.,Alenazi, Y.,Eaton, J.R.O.,Kawamura, A.,Shaw, J.,Proudfoot, A.E.I.,Dias, J.M.,Bhattacharya, S.
A knottin scaffold directs the CXC-chemokine-binding specificity of tick evasins.
J.Biol.Chem., 294:11199-11212, 2019

PubMed Abstract: Tick evasins (EVAs) bind either CC- or CXC-chemokines by a poorly understood promiscuous or "one-to-many" mechanism to neutralize inflammation. Because EVAs potently inhibit inflammation in many preclinical models, highlighting their potential as biological therapeutics for inflammatory diseases, we sought to further unravel the CXC-chemokine-EVA interactions. Using yeast surface display, we identified and characterized 27 novel CXC-chemokine-binding evasins homologous to EVA3 and defined two functional classes. The first, which included EVA3, exclusively bound ELR CXC-chemokines, whereas the second class bound both ELR and ELR CXC-chemokines, in several cases including CC-motif chemokine ligand 10 (CXCL10) but, surprisingly, not CXCL8. The X-ray crystal structure of EVA3 at a resolution of 1.79 Å revealed a single antiparallel β-sheet with six conserved cysteine residues forming a disulfide-bonded knottin scaffold that creates a contiguous solvent-accessible surface. Swapping analyses identified distinct knottin scaffold segments necessary for different CXC-chemokine-binding activities, implying that differential ligand positioning, at least in part, plays a role in promiscuous binding. Swapping segments also transferred chemokine-binding activity, resulting in a hybrid EVA with dual CXCL10- and CXCL8-binding activities. The solvent-accessible surfaces of the knottin scaffold segments have distinctive shape and charge, which we suggest drives chemokine-binding specificity. These studies provide structural and mechanistic insight into how CXC-chemokine-binding tick EVAs achieve class specificity but also engage in promiscuous binding.

PubMed: 31167786
DOI: 10.1074/jbc.RA119.008817

Experimental method

X-RAY DIFFRACTION (1.79 Å)