E-selectin ligand complexes adopt an extended high-affinity conformation

摘要: E-selectin is a cell-adhesion molecule of the vascular endothelium that promotes essential leukocyte rolling in early inflammatory response by binding to glycoproteins containing tetrasaccharide sialyl Lewis(x) (sLe(x)). Efficient recruitment under flow conditions depends on an increased lifetime E-selectin/ligand complexes tensile force so-called catch-bond mode. Co-crystal structures representative fragment extracellular region with sLe(x) and glycomimetic antagonist thereof reveal extended conformation, which identified as high-affinity state molecular dynamics simulations. Small-angle X-ray scattering experiments demonstrate direct link between ligand conformational transition static solution. This permits tracing series concerted structural changes connecting stretching basis catch-bond-mediated recruitment. The detailed view site paves way for design new generation selectin antagonists. special interest, since their therapeutic potential was recently demonstrated pan-selectin antagonists GMI-1070 (Rivipansel).