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 Lewisx(...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 Lewisx(sLex).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 sLex 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 potentialwas recently demonstrated with the pan-selectin antagonists GMI-1070(Rivipansel).展开更多
基金supported by the Swiss National Science Foundation(grant number 200020_129935 and R’EQUIP 145023).
文摘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 Lewisx(sLex).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 sLex 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 potentialwas recently demonstrated with the pan-selectin antagonists GMI-1070(Rivipansel).
