7SO0

Crystal Structure of the Engineered Tick Evasin EVA-P974(F31A) Complexed to Human Chemokine CCL2

Summary for 7SO0

• Entry DOI: 10.2210/pdb7so0/pdb
• Descriptor: Evasin P974, C-C motif chemokine 2 (3 entities in total)
• Functional Keywords: inflammation, chemokine, tick evasin, immune system
• Biological source: Amblyomma cajennense (Cayenne tick, Acarus cajennensis); More
• Total number of polymer chains: 2
• Total formula weight: 18298.99

Authors

Bhusal, R.P.,Devkota, S.R.,Aryal, P.,Wilce, M.C.J.,Stone, M.J. (deposition date: 2021-10-28, release date: 2022-03-16, Last modification date: 2024-10-23)

Primary citation

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.
Structure-guided engineering of tick evasins for targeting chemokines in inflammatory diseases.
Proc.Natl.Acad.Sci.USA, 119:-, 2022

PubMed 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.

PubMed: 35217625
DOI: 10.1073/pnas.2122105119

Experimental method

X-RAY DIFFRACTION (1.74 Å)