4CSY

E-selectin lectin, EGF-like and two SCR domains complexed with Sialyl Lewis X

Summary for 4CSY

• Entry DOI: 10.2210/pdb4csy/pdb
• Related: 4CSS 4CST
• Descriptor: E-SELECTIN, N-acetyl-alpha-neuraminic acid-(2-3)-beta-D-galactopyranose-(1-4)-[alpha-L-fucopyranose-(1-3)]methyl 2-acetamido-2-deoxy-beta-D-glucopyranoside, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: cell-adhesion, human lectin, c-type lectin, inflammation, leukocyte, sialyl lewis x, slex, protein conformation, ligand-induced conformational change, catch- bond, cell adhesion
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane ; Single-pass type I membrane protein: P16581
• Total number of polymer chains: 2
• Total formula weight: 67458.13

Authors

Preston, R.C.,Jakob, R.P.,Binder, F.P.C.,Sager, C.P.,Ernst, B.,Maier, T. (deposition date: 2014-03-11, release date: 2014-09-24, Last modification date: 2024-11-13)

Primary citation

Preston, R.C.,Jakob, R.P.,Binder, F.P.,Sager, C.P.,Ernst, B.,Maier, T.
E-Selectin Ligand Complexes Adopt an Extended High-Affinity Conformation.
J.Mol.Cell.Biol., 8:62-, 2016

PubMed 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).

PubMed: 26117840
DOI: 10.1093/JMCB/MJV046

Experimental method

X-RAY DIFFRACTION (2.41 Å)