title: The water network in galectin-3 ligand binding site guides inhibitor design.
abstract: 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.
authors: School of Life Sciences, Northeast Normal University, Changchun 130024, China.
authors: Jiyong
authors: J
authors: Su
authors: School of Life Sciences, Northeast Normal University, Changchun 130024, China.
authors: Tao
authors: T
authors: Zhang
authors: School of Life Sciences, Northeast Normal University, Changchun 130024, China.
authors: Peiqi
authors: P
authors: Wang
authors: School of Life Sciences, Northeast Normal University, Changchun 130024, China.
authors: Fengjian
authors: F
authors: Liu
authors: School of Life Sciences, Northeast Normal University, Changchun 130024, China.
authors: Guihua
authors: G
authors: Tai
authors: School of Life Sciences, Northeast Normal University, Changchun 130024, China zhouyf383@nenu.edu.cn.
authors: Yifa
authors: Y
authors: Zhou
mesh_terms: D001665:Binding Sites; D001798:Blood Proteins; D018360:Crystallography, X-Ray; D015195:Drug Design; D037502:Galectin 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D037161:Galectins; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity; D014867:Water / Q000737:chemistry
chemical_list: D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C428445:LGALS3 protein, human; D008024:Ligands; D011994:Recombinant Proteins; D014867:Water
keywords: co-crystal structure; drug design; galectin-3; lactose; water molecule