2XG3

Human galectin-3 in complex with a benzamido-N-acetyllactoseamine inhibitor

Summary for 2XG3

• Entry DOI: 10.2210/pdb2xg3/pdb
• Related: 1A3K 1KJL 1KJR
• Descriptor: Galectin-3, beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: ige-binding protein, lectin, sugar binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 16214.95

Authors

Diehl, C.,Engstrom, O.,Delaine, T.,Hakansson, M.,Genheden, S.,Modig, K.,Leffler, H.,Ryde, U.,Nilsson, U.,Akke, M. (deposition date: 2010-05-30, release date: 2010-10-13, Last modification date: 2024-05-01)

Primary citation

Diehl, C.,Engstrom, O.,Delaine, T.,Hakansson, M.,Genheden, S.,Modig, K.,Leffler, H.,Ryde, U.,Nilsson, U.J.,Akke, M.
Protein flexibility and conformational entropy in ligand design targeting the carbohydrate recognition domain of galectin-3.
J. Am. Chem. Soc., 132:14577-14589, 2010

PubMed Abstract: Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy.

PubMed: 20873837
DOI: 10.1021/ja105852y

Experimental method

X-RAY DIFFRACTION (1.2 Å)