Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Ziarek, Joshua J., Heroux, Maxime S., Veldkamp, Christopher T., Peterson, Francis C., Volkman, Brian F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Molecular Diversity Preservation International (MDPI) 2011
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
_version_ 1782207737691635712
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
work_keys_str_mv AT ziarekjoshuaj sulfotyrosinerecognitionasmarkerfordruggablesitesintheextracellularspace
AT herouxmaximes sulfotyrosinerecognitionasmarkerfordruggablesitesintheextracellularspace
AT veldkampchristophert sulfotyrosinerecognitionasmarkerfordruggablesitesintheextracellularspace
AT petersonfrancisc sulfotyrosinerecognitionasmarkerfordruggablesitesintheextracellularspace
AT volkmanbrianf sulfotyrosinerecognitionasmarkerfordruggablesitesintheextracellularspace