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Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space
Chemokine signaling is a well-known agent of autoimmune disease, HIV infection, and cancer. Drug discovery efforts for these signaling molecules have focused on developing inhibitors targeting their associated G protein-coupled receptors. Recently, we used a structure-based approach directed at the...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Molecular Diversity Preservation International (MDPI)
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131587/ https://www.ncbi.nlm.nih.gov/pubmed/21747703 http://dx.doi.org/10.3390/ijms12063740 |
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author | Ziarek, Joshua J. Heroux, Maxime S. Veldkamp, Christopher T. Peterson, Francis C. Volkman, Brian F. |
author_facet | Ziarek, Joshua J. Heroux, Maxime S. Veldkamp, Christopher T. Peterson, Francis C. Volkman, Brian F. |
author_sort | Ziarek, Joshua J. |
collection | PubMed |
description | Chemokine signaling is a well-known agent of autoimmune disease, HIV infection, and cancer. Drug discovery efforts for these signaling molecules have focused on developing inhibitors targeting their associated G protein-coupled receptors. Recently, we used a structure-based approach directed at the sulfotyrosine-binding pocket of the chemokine CXCL12, and thereby demonstrated that small molecule inhibitors acting upon the chemokine ligand form an alternative therapeutic avenue. Although the 50 members of the chemokine family share varying degrees of sequence homology (some as little as 20%), all members retain the canonical chemokine fold. Here we show that an equivalent sulfotyrosine-binding pocket appears to be conserved across the chemokine superfamily. We monitored sulfotyrosine binding to four representative chemokines by NMR. The results suggest that most chemokines harbor a sulfotyrosine recognition site analogous to the cleft on CXCL12 that binds sulfotyrosine 21 of the receptor CXCR4. Rational drug discovery efforts targeting these sites may be useful in the development of specific as well as broad-spectrum chemokine inhibitors. |
format | Online Article Text |
id | pubmed-3131587 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Molecular Diversity Preservation International (MDPI) |
record_format | MEDLINE/PubMed |
spelling | pubmed-31315872011-07-11 Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space Ziarek, Joshua J. Heroux, Maxime S. Veldkamp, Christopher T. Peterson, Francis C. Volkman, Brian F. Int J Mol Sci Article Chemokine signaling is a well-known agent of autoimmune disease, HIV infection, and cancer. Drug discovery efforts for these signaling molecules have focused on developing inhibitors targeting their associated G protein-coupled receptors. Recently, we used a structure-based approach directed at the sulfotyrosine-binding pocket of the chemokine CXCL12, and thereby demonstrated that small molecule inhibitors acting upon the chemokine ligand form an alternative therapeutic avenue. Although the 50 members of the chemokine family share varying degrees of sequence homology (some as little as 20%), all members retain the canonical chemokine fold. Here we show that an equivalent sulfotyrosine-binding pocket appears to be conserved across the chemokine superfamily. We monitored sulfotyrosine binding to four representative chemokines by NMR. The results suggest that most chemokines harbor a sulfotyrosine recognition site analogous to the cleft on CXCL12 that binds sulfotyrosine 21 of the receptor CXCR4. Rational drug discovery efforts targeting these sites may be useful in the development of specific as well as broad-spectrum chemokine inhibitors. Molecular Diversity Preservation International (MDPI) 2011-06-08 /pmc/articles/PMC3131587/ /pubmed/21747703 http://dx.doi.org/10.3390/ijms12063740 Text en © 2011 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0 This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Ziarek, Joshua J. Heroux, Maxime S. Veldkamp, Christopher T. Peterson, Francis C. Volkman, Brian F. Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space |
title | Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space |
title_full | Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space |
title_fullStr | Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space |
title_full_unstemmed | Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space |
title_short | Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space |
title_sort | sulfotyrosine recognition as marker for druggable sites in the extracellular space |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131587/ https://www.ncbi.nlm.nih.gov/pubmed/21747703 http://dx.doi.org/10.3390/ijms12063740 |
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