The water network in galectin-3 ligand binding site guides inhibitor design

Acta Biochim Biophys Sin (Shanghai). 2015 Mar;47(3):192-8. doi: 10.1093/abbs/gmu132. Epub 2015 Feb 5.


Galectin-3 (Gal-3) which shows affinity of β-galactosides is a cancer-related protein. Thus, it is important to understand its ligand binding mechanism and then design its specific inhibitor. It was suggested that the positions of water molecules in Gal-3 ligand-binding site could be replaced by appropriate chemical groups of ideal inhibitors. However, the reported structures of Gal-3 carbohydrate recognition domain (CRD) complexed with lactose showed that the number of water molecules are different and the water positions are inconsistent in the ligand-binding site. This study reported four high-resolution (1.24-1.19 Å) structures of Gal-3 CRD complexed with lactose, and accurately located 12 conserved water molecules in the water network of Gal-3 CRD ligand-binding site by merging these structures. These water molecules either directly stabilize the binding of Gal-3 CRD and lactose, or hold the former water molecules at the right place. In particular, water molecule 4 (W4) which only coordinates with water molecule 5 (W5) and water molecule 6 (W6) plays a key role in stabilizing galactose residue. In addition, by three-dimensional alignment of the positions of all residues, 14 flexible parts of Gal-3 CRD were found to dynamically fluctuate in the crystalline environment.

Keywords: co-crystal structure; drug design; galectin-3; lactose; water molecule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Blood Proteins
  • Crystallography, X-Ray
  • Drug Design
  • Galectin 3 / antagonists & inhibitors*
  • Galectin 3 / chemistry*
  • Galectin 3 / metabolism
  • Galectins
  • Humans
  • Ligands
  • Models, Molecular
  • Protein Conformation
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Static Electricity
  • Water / chemistry


  • Blood Proteins
  • Galectin 3
  • Galectins
  • LGALS3 protein, human
  • Ligands
  • Recombinant Proteins
  • Water