Double affinity amplification of galectin-ligand interactions through arginine-arene interactions: Synthetic, thermodynamic, and computational studies with aromatic diamido thiodigalactosides

被引:80
作者
Cumpstey, Ian [1 ]
Salomonsson, Emma [2 ]
Sundin, Anders [1 ]
Leffler, Hakon [2 ]
Nilsson, Ulf J. [1 ]
机构
[1] Lund Univ, S-22100 Lund, Sweden
[2] Lund Univ, Dept Lab Med, Sect MIG, S-22362 Lund, Sweden
关键词
carbohydrates; galectin; inhibitors; thioglycosides;
D O I
10.1002/chem.200701932
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
A series of aromatic mono-Computational studies were employed or diamido-thiodigalactoside deriva- to explain binding preferences for the lives were synthesized and studied as ligands for galectin-1, -3, -7, -8N terminal domain, and -9N terminal domain. The affinity determination in vitro with competitive fluorescence-polarization experiments and thermodynamic analysis by isothermal microcalorimetry provided a coherent picture of structural requirements for arginine-arene interactions in galectin-ligand binding. different galectins. Galectin-3 formed two almost ideal arene-arginine stacking interactions according to computer modeling and also had the highest affinity for the diamido-thiodigalactosides (K-d below 50 nM). Site-directed mutagenesis of galectin-3 arginines involved in binding corroborated the importance of their interaction with the aromatic diamido-thiodigalactosides. Furthermore, the arginine mutants revealed distinct differences between free, flexible, and solvent-exposed arginine side chains and tightly ion-paired arginine side chains in interactions with aromatic systems.
引用
收藏
页码:4233 / 4245
页数:13
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