1KJL

High Resolution X-Ray Structure of Human Galectin-3 in complex with LacNAc

1KJL の概要

• エントリーDOI: 10.2210/pdb1kjl/pdb
• 関連するPDBエントリー: 1A3K 1KJR
• 分子名称: Galectin-3, beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: lacnac complex, sugar binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16950.38

構造登録者

Sorme, P.,Arnoux, P.,Kahl-Knutsson, B.,Leffler, H.,Rini, J.M.,Nilsson, U.J. (登録日: 2001-12-04, 公開日: 2005-04-12, 最終更新日: 2023-08-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.4 Å)