8R5L

E-selectin complexed with glycomimetic ligand BW850

Summary for 8R5L

• Entry DOI: 10.2210/pdb8r5l/pdb
• Descriptor: E-selectin, 2-acetamido-2-deoxy-beta-D-glucopyranose, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: sickle cell, vaso-occlusive crisis (voc), rivipansel, sickle cell disease (scd), cell adhesion
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34194.68

Authors

Jakob, R.P.,Ernst, B.,Maier, T. (deposition date: 2023-11-17, release date: 2024-10-23)

Primary citation

Wagner, B.,Smiesko, M.,Jakob, R.P.,Muhlethaler, T.,Cramer, J.,Maier, T.,Rabbani, S.,Schwardt, O.,Ernst, B.
Analogues of the pan-selectin antagonist rivipansel (GMI-1070).
Eur.J.Med.Chem., 272:116455-116455, 2024

PubMed Abstract: The selectin family consisting of E-, P- and L-selectin plays dominant roles in atherosclerosis, ischemia-reperfusion injury, inflammatory diseases, and metastatic spreading of some cancers. An early goal in selectin-targeted drug discovery campaigns was to identify ligands binding to all three selectins, so-called pan-selectin antagonists. The physiological epitope, tetrasaccharide sialyl Lewis (sLe, 1) binds to all selectins, albeit with very different affinities. Whereas P- and L-selectin require additional interactions contributed by sulfate groups for high binding affinity, E-selectin can functionally bind sLe-modified glycolipids and glycoproteins. Rivipansel (3) marked the first pan-selectin antagonist, which simultaneously interacted with both the sLe and the sulfate binding site. The aim of this contribution was to improve the pan-selectin affinity of rivipansel (3) by leveraging a new class of sLe mimetics in combination with an optimized linker length to the sulfate bearing group. As a result, the pan-selectin antagonist 11b exhibits an approximatively 5-fold improved affinity for E-, as well as P-selectin.

PubMed: 38728868
DOI: 10.1016/j.ejmech.2024.116455

Experimental method

X-RAY DIFFRACTION (2.2 Å)