Conformational Selection in Glycomimetics: Human Galectin‐1 Only Recognizes syn‐Ψ‐Type Conformations of β‐1,3‐Linked Lactose and Its C‐Glycosyl Derivative

Abstract

The human lectin galectin-1 (hGal-1) translates sugar signals, that is, β-galactosides, into effects on the level of cells, for example, growth regulation, and has become a model for studying binding of biopharmaceutically relevant derivatives. Bound-state conformations of Galβ-C-(1→3)-Glcβ-OMe (1) and its βGal-(1→3)-βGlc-OMe disaccharide parent compound were studied by using NMR spectroscopy (transferred (TR)-NOESY data), assisted by docking experiments and molecular dynamics (MD) simulations. The molecular recognition process involves a conformational selection event. Although free C-glycoside access four distinct conformers in solution, hGal-1 recognizes shape of a local minimum of compound 1, the syn-Φ/syn-Ψ conformer, not the structure at global minimum. MD simulations were run to explain, in structural terms, the observed geometry of the complex.

Structural Basis Underlying the Binding Preference of Human Galectins-1, -3 and -7 for Galβ1-3/4GlcNAc

“…The average ψ LN1 (135°, defined by C1 GAL –O3 GlcNAc –C3 GlcNAc –C4 GlcNAc of LN1) is dramatically different from the average ψ LN2 (-108°, defined by C1 GAL –O4 GlcNAc –C4 GlcNAc –C5 GlcNAc of LN2). This ~240° shift allows the three important OH groups of galectin-bound LN1 (C4-OH and C6-OH of Gal and C4-OH of GlcNAc) to form the binding interactions not only essential for the gelectin recognition, but also homologous to those produced by the OH groups of galectin-bound LN2 (C4-OH and C6-OH of Gal and C3-OH of GlcNAc) ( Fig 2D ) [ 10 , 37 , 38 ]. The glycosidic torsional angles in this study were defined in previous reports [ 16 , 36 ].…”

Conformational Plasticity in Glycomimetics: Fluorocarbamethyl‐L‐idopyranosides Mimic the Intrinsic Dynamic Behaviour of Natural Idose Rings

“…carbon, sulfur, nitrogen). [10,11] However,t heir conformational preferences, as well as their internal hydrogenbond patterns, might differ from their natural analogues in aw ay that could also influence their interactions with the key residues within the binding site of sugar receptors. [12] For instance, for carbasugars, for which the ring oxygen hasb een replaced by am ethylene group, [13] this substitution rules out the anomeric effects, modifies the intramolecularh ydrogen-bond pattern, modulates the amphiphilicity of the sugar ring, and results in changes in the flexibility and conformations population distributions.…”

“…Generally speaking, two major groups of sugar mimics have been devised by substitution of either the endo ‐ or exo ‐cyclic oxygen atom by another atom (e.g. carbon, sulfur, nitrogen) 10. 11 However, their conformational preferences, as well as their internal hydrogen‐bond patterns, might differ from their natural analogues in a way that could also influence their interactions with the key residues within the binding site of sugar receptors 12.…”

Advanced NMR Techniques: Defining Carbohydrate Structures and Ligand–Receptor Interactions

“…In this manner, information about the dynamics and flexibility of both ligand and protein during the complex formation, as well as about the interactions established between them and their evolution through time can be derived [95]. The MD simulations can be linked to other methods, such as molecular mechanic (MM)/Poisson-Boltzmann surface area (PBSA), which allows decomposing the binding energy in its components per residue giving the weight of its implication in the interaction [96].…”