Structure-guided engineering of tick evasins for targeting chemokines in inflammatory diseases
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(Published version)
Date
2022
Authors
Bhusal, R.P.
Aryal, P.
Devkota, S.R.
Pokhrel, R.
Gunzburg, M.J.
Foster, S.R.
Lim, H.D.
Payne, R.J.
Wilce, M.C.J.
Stone, M.J.
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Journal article
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Proceedings of the National Academy of Sciences of the United States of America, 2022; 119(9):e2122105119-1-e2122105119-7
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Ram Prasad Bhusal, Pramod Aryal, Shankar Raj Devkota, Rina Pokhrel, Menachem J. Gunzburg, Simon R. Foster, Herman D. Lim, Richard J. Payne, Matthew C. J. Wilce, and Martin J. Stone
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Abstract
As natural chemokine inhibitors, evasin proteins produced in tick saliva are potential therapeutic agents for numerous inflammatory diseases. Engineering evasins to block the desired chemokines and avoid off-target side effects requires structural understanding of their target selectivity. Structures of the class A evasin EVA-P974 bound to human CC chemokine ligands 7 and 17 (CCL7 and CCL17) and to a CCL8-CCL7 chimera reveal that the specificity of class A 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 four hotspots in flexible structural elements. Hotspot mutations alter target preference, enabling inhibition of selected chemokines. The structure of an engineered EVA-P974 bound to CCL2 reveals an underlying molecular mechanism of EVA-P974 target preference. These results provide a structure-based framework for engineering evasins as targeted antiinflammatory therapeutics.
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Published February 25, 2022
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© 2022 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial- NoDerivatives License 4.0 (CC BY-NC-ND).