Fine specificity of galectins: Molecular mechanism, cellular function and design of inhibitors

CARB 15

Hakon Leffler, hakon.leffler@med.lu.se1, S. Carlsson1, E. Salomonsson1, Michael Carlsson1, C. Cederfur1, B. Kahl-Knutson1, Y. Qian1, J. Tejler2, C. Oberg2, and UJ. Nilsson2. (1) Department of Laboratory Medicine, Sect. MIG (Microbiology, Immunology, Glycobiology), Lund University, Lund, 22362, Sweden, (2) Department of Organic Chemistry, Lund University, Lund, Sweden
The galectin ligand binding site can be modelled as having five subsites A-E, where site C is conserved and gives the common affinity for ƒ"-galactose, whereas the others vary and give variable fine specificity. Site B, for example, gives galectin-8 uniquely high affinity (Kd ~100 nM) for NeuAcƒÑ2-3Lactose. This is not needed, however, for galectin-8 binding to a cell surface, since combined interaction with second best ligands of moderate affinity is enough. Instead, the fine specificity appears to determine the intracellular fate of galectin-8 and other galectins after endocytosis. This fate may fine tune intracellular targeting of other molecules and thereby their signalling, which in turn may affect higher level cellular activities in cancer and inflammation. For further studies, galectin mutants with altered fine specificity were generated, and, based on models of ligand interaction in sites B-D, potent galectin inhibitors were designed as research tools and leads to future therapeutics.
 

Galectins: Structures, Functions and Therapeutic Targets
9:00 AM-12:10 PM, Monday, August 20, 2007 BCEC -- 162B, Oral

Division of Carbohydrate Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007