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Engineering broad-spectrum inhibitors of inflammatory chemokines from subclass A3 tick evasins

Chemokines are key regulators of leukocyte trafficking and attractive targets for anti-inflammatory therapy. Evasins are chemokine-binding proteins from tick saliva, whose application as anti-inflammatory therapeutics will require manipulation of their chemokine target selectivity. Here we describe...

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Autores principales: Devkota, Shankar Raj, Aryal, Pramod, Pokhrel, Rina, Jiao, Wanting, Perry, Andrew, Panjikar, Santosh, Payne, Richard J., Wilce, Matthew C. J., Bhusal, Ram Prasad, Stone, Martin J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349104/
https://www.ncbi.nlm.nih.gov/pubmed/37452046
http://dx.doi.org/10.1038/s41467-023-39879-3
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author Devkota, Shankar Raj
Aryal, Pramod
Pokhrel, Rina
Jiao, Wanting
Perry, Andrew
Panjikar, Santosh
Payne, Richard J.
Wilce, Matthew C. J.
Bhusal, Ram Prasad
Stone, Martin J.
author_facet Devkota, Shankar Raj
Aryal, Pramod
Pokhrel, Rina
Jiao, Wanting
Perry, Andrew
Panjikar, Santosh
Payne, Richard J.
Wilce, Matthew C. J.
Bhusal, Ram Prasad
Stone, Martin J.
author_sort Devkota, Shankar Raj
collection PubMed
description Chemokines are key regulators of leukocyte trafficking and attractive targets for anti-inflammatory therapy. Evasins are chemokine-binding proteins from tick saliva, whose application as anti-inflammatory therapeutics will require manipulation of their chemokine target selectivity. Here we describe subclass A3 evasins, which are unique to the tick genus Amblyomma and distinguished from “classical” class A1 evasins by an additional disulfide bond near the chemokine recognition interface. The A3 evasin EVA-AAM1001 (EVA-A) bound to CC chemokines and inhibited their receptor activation. Unlike A1 evasins, EVA-A was not highly dependent on N- and C-terminal regions to differentiate chemokine targets. Structures of chemokine-bound EVA-A revealed a deep hydrophobic pocket, unique to A3 evasins, that interacts with the residue immediately following the CC motif of the chemokine. Mutations to this pocket altered the chemokine selectivity of EVA-A. Thus, class A3 evasins provide a suitable platform for engineering proteins with applications in research, diagnosis or anti-inflammatory therapy.
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spelling pubmed-103491042023-07-16 Engineering broad-spectrum inhibitors of inflammatory chemokines from subclass A3 tick evasins Devkota, Shankar Raj Aryal, Pramod Pokhrel, Rina Jiao, Wanting Perry, Andrew Panjikar, Santosh Payne, Richard J. Wilce, Matthew C. J. Bhusal, Ram Prasad Stone, Martin J. Nat Commun Article Chemokines are key regulators of leukocyte trafficking and attractive targets for anti-inflammatory therapy. Evasins are chemokine-binding proteins from tick saliva, whose application as anti-inflammatory therapeutics will require manipulation of their chemokine target selectivity. Here we describe subclass A3 evasins, which are unique to the tick genus Amblyomma and distinguished from “classical” class A1 evasins by an additional disulfide bond near the chemokine recognition interface. The A3 evasin EVA-AAM1001 (EVA-A) bound to CC chemokines and inhibited their receptor activation. Unlike A1 evasins, EVA-A was not highly dependent on N- and C-terminal regions to differentiate chemokine targets. Structures of chemokine-bound EVA-A revealed a deep hydrophobic pocket, unique to A3 evasins, that interacts with the residue immediately following the CC motif of the chemokine. Mutations to this pocket altered the chemokine selectivity of EVA-A. Thus, class A3 evasins provide a suitable platform for engineering proteins with applications in research, diagnosis or anti-inflammatory therapy. Nature Publishing Group UK 2023-07-14 /pmc/articles/PMC10349104/ /pubmed/37452046 http://dx.doi.org/10.1038/s41467-023-39879-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Devkota, Shankar Raj
Aryal, Pramod
Pokhrel, Rina
Jiao, Wanting
Perry, Andrew
Panjikar, Santosh
Payne, Richard J.
Wilce, Matthew C. J.
Bhusal, Ram Prasad
Stone, Martin J.
Engineering broad-spectrum inhibitors of inflammatory chemokines from subclass A3 tick evasins
title Engineering broad-spectrum inhibitors of inflammatory chemokines from subclass A3 tick evasins
title_full Engineering broad-spectrum inhibitors of inflammatory chemokines from subclass A3 tick evasins
title_fullStr Engineering broad-spectrum inhibitors of inflammatory chemokines from subclass A3 tick evasins
title_full_unstemmed Engineering broad-spectrum inhibitors of inflammatory chemokines from subclass A3 tick evasins
title_short Engineering broad-spectrum inhibitors of inflammatory chemokines from subclass A3 tick evasins
title_sort engineering broad-spectrum inhibitors of inflammatory chemokines from subclass a3 tick evasins
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349104/
https://www.ncbi.nlm.nih.gov/pubmed/37452046
http://dx.doi.org/10.1038/s41467-023-39879-3
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