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E-selectin ligand complexes adopt an extended high-affinity conformation
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 3157890
Author(s) Preston, Roland C.; Jakob, Roman P.; Binder, Florian P. C.; Sager, Christoph P.; Ernst, Beat; Maier, Timm
Author(s) at UniBasel Maier, Timm
Ernst, Beat
Preston, Roland
Jakob, Roman Peter
Sager, Christoph
Binder, Florian
Year 2016
Year: comment Epub 2015 Jun 27.
Title E-selectin ligand complexes adopt an extended high-affinity conformation
Journal Journal of Molecular Cell Biology
Volume 8
Number 1
Pages / Article-Number 62-72
Abstract 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).
Publisher Oxford University Press
ISSN/ISBN 1674-2788 ; 1759-4685
edoc-URL http://edoc.unibas.ch/39420/
Full Text on edoc Available
Digital Object Identifier DOI 10.1093/jmcb/mjv046
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/26117840
ISI-Number WOS:000372615600007
Document type (ISI) Journal Article
 
   

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