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E-selectin ligand complexes adopt an extended high-affinity conformation
E-selectin is a cell-adhesion molecule of the vascular endothelium that promotes essential leukocyte rolling in the early inflammatory response by binding to glycoproteins containing the tetrasaccharide sialyl Lewis(x) (sLe(x)). Efficient leukocyte recruitment under vascular flow conditions depends...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710209/ https://www.ncbi.nlm.nih.gov/pubmed/26117840 http://dx.doi.org/10.1093/jmcb/mjv046 |
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author | Preston, Roland C. Jakob, Roman P. Binder, Florian P.C. Sager, Christoph P. Ernst, Beat Maier, Timm |
author_facet | Preston, Roland C. Jakob, Roman P. Binder, Florian P.C. Sager, Christoph P. Ernst, Beat Maier, Timm |
author_sort | Preston, Roland C. |
collection | PubMed |
description | E-selectin is a cell-adhesion molecule of the vascular endothelium that promotes essential leukocyte rolling in the early inflammatory response by binding to glycoproteins containing the tetrasaccharide sialyl Lewis(x) (sLe(x)). Efficient leukocyte recruitment under vascular flow conditions depends on an increased lifetime of E-selectin/ligand complexes under tensile force in a so-called catch-bond binding mode. Co-crystal structures of a representative fragment of the extracellular E-selectin region with sLe(x) and a glycomimetic antagonist thereof reveal an extended E-selectin conformation, which is identified as a high-affinity binding state of E-selectin by molecular dynamics simulations. Small-angle X-ray scattering experiments demonstrate a direct link between ligand binding and E-selectin conformational transition under static conditions in solution. This permits tracing a series of concerted structural changes connecting ligand binding to conformational stretching as the structural basis of E-selectin catch-bond-mediated leukocyte recruitment. The detailed molecular view of the binding site paves the way for the design of a new generation of selectin antagonists. This is of special interest, since their therapeutic potential was recently demonstrated with the pan-selectin antagonists GMI-1070 (Rivipansel). |
format | Online Article Text |
id | pubmed-4710209 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-47102092016-01-13 E-selectin ligand complexes adopt an extended high-affinity conformation Preston, Roland C. Jakob, Roman P. Binder, Florian P.C. Sager, Christoph P. Ernst, Beat Maier, Timm J Mol Cell Biol Articles E-selectin is a cell-adhesion molecule of the vascular endothelium that promotes essential leukocyte rolling in the early inflammatory response by binding to glycoproteins containing the tetrasaccharide sialyl Lewis(x) (sLe(x)). Efficient leukocyte recruitment under vascular flow conditions depends on an increased lifetime of E-selectin/ligand complexes under tensile force in a so-called catch-bond binding mode. Co-crystal structures of a representative fragment of the extracellular E-selectin region with sLe(x) and a glycomimetic antagonist thereof reveal an extended E-selectin conformation, which is identified as a high-affinity binding state of E-selectin by molecular dynamics simulations. Small-angle X-ray scattering experiments demonstrate a direct link between ligand binding and E-selectin conformational transition under static conditions in solution. This permits tracing a series of concerted structural changes connecting ligand binding to conformational stretching as the structural basis of E-selectin catch-bond-mediated leukocyte recruitment. The detailed molecular view of the binding site paves the way for the design of a new generation of selectin antagonists. This is of special interest, since their therapeutic potential was recently demonstrated with the pan-selectin antagonists GMI-1070 (Rivipansel). Oxford University Press 2016-02 2015-06-27 /pmc/articles/PMC4710209/ /pubmed/26117840 http://dx.doi.org/10.1093/jmcb/mjv046 Text en © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Articles Preston, Roland C. Jakob, Roman P. Binder, Florian P.C. Sager, Christoph P. Ernst, Beat Maier, Timm E-selectin ligand complexes adopt an extended high-affinity conformation |
title | E-selectin ligand complexes adopt an extended high-affinity conformation |
title_full | E-selectin ligand complexes adopt an extended high-affinity conformation |
title_fullStr | E-selectin ligand complexes adopt an extended high-affinity conformation |
title_full_unstemmed | E-selectin ligand complexes adopt an extended high-affinity conformation |
title_short | E-selectin ligand complexes adopt an extended high-affinity conformation |
title_sort | e-selectin ligand complexes adopt an extended high-affinity conformation |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710209/ https://www.ncbi.nlm.nih.gov/pubmed/26117840 http://dx.doi.org/10.1093/jmcb/mjv046 |
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