1KJR

Crystal Structure of the human galectin-3 CRD in complex with a 3'-derivative of N-Acetyllactosamine

Summary for 1KJR

• Entry DOI: 10.2210/pdb1kjr/pdb
• Related: 1A3K 1KJL
• Descriptor: Galectin-3, beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2,3,5,6-TETRAFLUORO-4-METHOXY-BENZAMIDE, ... (5 entities in total)
• Functional Keywords: all beta, sugar binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 17013.69

Authors

Sorme, P.,Arnoux, P.,Kahl-Knutsson, B.,Leffler, H.,Rini, J.M.,Nilsson, U.J. (deposition date: 2001-12-05, release date: 2005-04-12, Last modification date: 2024-02-14)

Primary citation

Sorme, P.,Arnoux, P.,Kahl-Knutsson, B.,Leffler, H.,Rini, J.M.,Nilsson, U.J.
Structural and thermodynamic studies on cation-Pi interactions in lectin-ligand complexes: high-affinity galectin-3 inhibitors through fine-tuning of an arginine-arene interaction.
J.Am.Chem.Soc., 127:1737-1743, 2005

PubMed Abstract: The high-resolution X-ray crystal structures of the carbohydrate recognition domain of human galectin-3 were solved in complex with N-acetyllactosamine (LacNAc) and the high-affinity inhibitor, methyl 2-acetamido-2-deoxy-4-O-(3-deoxy-3-[4-methoxy-2,3,5,6-tetrafluorobenzamido]-beta-D-galactopyranose)-beta-D-glucopyranoside, to gain insight into the basis for the affinity-enhancing effect of the 4-methoxy-2,3,5,6-tetrafluorobenzamido moiety. The structures show that the side chain of Arg144 stacks against the aromatic moiety of the inhibitor, an interaction made possible by a reorientation of the side chain relative to that seen in the LacNAc complex. Based on these structures, synthesis of second generation LacNAc derivatives carrying aromatic amides at 3'-C, followed by screening with a novel fluorescence polarization assay, has led to the identification of inhibitors with further enhanced affinity for galectin-3 (K(d) > or = 320 nM). The thermodynamic parameters describing the binding of the galectin-3 C-terminal to selected inhibitors were determined by isothermal titration calorimetry and showed that the affinity enhancements were due to favorable enthalpic contributions. These enhancements could be rationalized by the combined effects of the inhibitor aromatic structure on a cation-Pi interaction and of direct interactions between the aromatic substituents and the protein. The results demonstrate that protein-ligand interactions can be significantly enhanced by the fine-tuning of arginine-arene interactions.

PubMed: 15701008
DOI: 10.1021/ja043475p

Experimental method

X-RAY DIFFRACTION (1.55 Å)