6EYK

E-selectin lectin, EGF-like and two SCR domains complexed with glycomimetic ligand NV355

Summary for 6EYK

• Entry DOI: 10.2210/pdb6eyk/pdb
• Descriptor: E-selectin, 2-acetamido-2-deoxy-beta-D-glucopyranose, (2~{S})-3-cyclohexyl-2-[(2~{R},3~{S},4~{S},5~{R},6~{R})-2-(hydroxymethyl)-6-[(1~{R},2~{R},3~{S})-3-methyl-2-[(2~{R},3~{S},4~{R},5~{S},6~{R})-3,4,5-tris(oxidanyl)-6-(trifluoromethyl)oxan-2-yl]oxy-cyclohexyl]oxy-3,5-bis(oxidanyl)oxan-4-yl]oxy-propanoic acid, ... (5 entities in total)
• Functional Keywords: cell adhesion, cell-adhesion molecule, c-type lectin, inflammation, leukocyte, glycomimetic, catch-bond
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33581.02

Authors

Jakob, R.P.,Zihlmann, P.,Preston, R.C.,Varga, N.,Ernst, B.,Maier, T. (deposition date: 2017-11-13, release date: 2018-11-21, Last modification date: 2024-11-27)

Primary citation

Varga, N.,Smiesko, M.,Jiang, X.,Jakob, R.P.,Wagner, B.,Muhlethaler, T.,Datwyler, P.,Zihlmann, P.,Rabbani, S.,Maier, T.,Schwardt, O.,Ernst, B.
Strengthening an Intramolecular Non-Classical Hydrogen Bond to Get in Shape for Binding.
Angew.Chem.Int.Ed.Engl., 63:e202406024-e202406024, 2024

PubMed Abstract: In this research article, we report on the strengthening of a non-classical hydrogen bond (C-H⋅⋅⋅O) by introducing electron withdrawing groups at the carbon atom. The approach is demonstrated on the example of derivatives of the physiological E-selectin ligand sialyl Lewis (1, sLe). Its affinity is mainly due to a beneficial entropy term, which is predominantly caused by the pre-organization of sLe in its binding conformation. We have shown, that among the elements responsible for the pre-organization, the stabilization by a non-classical hydrogen bond between the H-C5 of l-fucose and the ring oxygen O5 of the neighboring d-galactose moiety is essential and yields 7.4 kJ mol. This effect could be further strengthened by replacing l-fucose by 6,6,6-trifluoro-l-fucose leading to an improved non-classical H-bond of 14.9 kJ mol, i.e., an improved pre-organization in the bioactive conformation. For a series of glycomimetics of sLe (1), this outcome could be confirmed by high field NMR-shifts of the H-C5, by X-ray diffraction analysis of glycomimetics co-crystallized with E-selectin as well as by isothermal titration calorimetry. Furthermore, the electron-withdrawing character of the CF-group beneficially influences the pharmacokinetic properties of sLe mimetics. Thus, acid-stability, a prerequisite for gastrointestinal stability, could be substantially improved.

PubMed: 39072885
DOI: 10.1002/anie.202406024

Experimental method

X-RAY DIFFRACTION (2.21 Å)