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

• Published in: Chemistry : a European journal Vol. 19; no. 43; pp. 14581 - 14590
• Main Authors: Vidal, Paloma, Roldós, Virginia, Fernández-Alonso, María del Carmen, Vauzeilles, Boris, Bleriot, Yves, Cañada, F. Javier, André, Sabine, Gabius, Hans-Joachim, Jiménez-Barbero, Jesús, Espinosa, Juan Félix, Martín-Santamaría, Sonsoles
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 18.10.2013; WILEY‐VCH Verlag; Wiley-VCH Verlag
• Subjects: Catalysis; Chemical Sciences; conformation analysis; Galectin 1 - chemistry; Galectin 1 - metabolism; glycoconjugates; Glycomics; Glycosides - chemistry; Humans; Hydrogen Bonding; Lactose - chemistry; Molecular Conformation; Molecular Dynamics Simulation; molecular modeling; NMR spectroscopy; Organic chemistry; Other; structure-activity relationships; Substrate Specificity; conformation analysis; structure-activity relationships; NMR spectroscopy; molecular modeling; glycoconjugates
• DOI: 10.1002/chem.201301244
• ISSN: 0947-6539

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. Trapping one conformer: Combination of transferred (TR)‐NOESY experiments, which include the bioactive conformation determination with molecular modeling, have enabled the explanation, in structural chemistry terms, of a conformational selection process in the recognition of C‐glycomimetics by a human galectin (see figure).