Conformational Selection in Glycomimetics: Human Galectin-1 Only Recognizes syn-Ψ-Type Conformations of β-1,3-Linked Lactose and Its C-Glycosyl Derivative
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)...
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Published in | Chemistry : a European journal Vol. 19; no. 43; pp. 14581 - 14590 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Weinheim
WILEY-VCH Verlag
18.10.2013
WILEY‐VCH Verlag Wiley-VCH Verlag |
Subjects | |
Online Access | Get full text |
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Summary: | 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). |
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Bibliography: | ArticleID:CHEM201301244 istex:970687E1309154A53A01E1102849AE24B860C502 European Commission - No. BM1003; No. CM1102 Comunidad de Madrid GLYCOPHARM ITN-project Fundación Universitaria San Pablo CEU - No. USP-PC 14/2011 and 13/2012 ark:/67375/WNG-932HMSVB-Q Spanish MINECO - No. CTQ2009-08536; No. CTQ2012-32025; No. CTQ2011-22724 GlycoHIT program - No. 260600 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0947-6539 1521-3765 |
DOI: | 10.1002/chem.201301244 |