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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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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. |
format | Online Article Text |
id | pubmed-10349104 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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