6W4Z

Galectin-8N terminal domain in complex with Methyl 3-O-[3-O-benzyloxy]-malonyl-beta-D-galactopyranoside

Summary for 6W4Z

• Entry DOI: 10.2210/pdb6w4z/pdb
• Descriptor: Galectin-8, methyl 3-O-[3-(benzyloxy)-3-oxopropanoyl]-beta-D-galactopyranoside, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: galectin-8n, sugar binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 35678.37

Authors

Patel, B.,Kishor, C.,Blanchard, H. (deposition date: 2020-03-12, release date: 2020-09-02, Last modification date: 2023-10-18)

Primary citation

Patel, B.,Kishor, C.,Houston, T.A.,Shatz-Azoulay, H.,Zick, Y.,Vinik, Y.,Blanchard, H.
Rational Design and Synthesis of Methyl-beta-d-galactomalonyl Phenyl Esters as Potent Galectin-8 N Antagonists.
J.Med.Chem., 63:11573-11584, 2020

PubMed Abstract: Galectin-8 is a β-galactoside-recognizing protein having an important role in the regulation of bone remodeling and cancer progression and metastasis. Methyl β-d-galactopyranoside malonyl aromatic esters have been designed to target and engage with particular amino acid residues of the galectin-8 extended carbohydrate-binding site. The chemically synthesized compounds had binding affinity toward galectin-8 in the range of 5-33 μM, as evaluated by isothermal titration calorimetry. This affinity directly correlated with the compounds' ability to inhibit galectin-8-induced expression of chemokines and proinflammatory cytokines in the SUM159 breast cancer cell line. X-ray crystallographic structure determination revealed that these monosaccharide-based compounds bind galectin-8 by engaging its unique arginine (Arg59) and simultaneously cross-linking to another arginine (Arg45) located across the carbohydrate-binding site. This structure-based drug design approach has led to the discovery of novel monosaccharide galactose-based antagonists, with the strongest-binding compound ( 5.72 μM) holding 7-fold tighter than the disaccharide lactose.

PubMed: 32809817
DOI: 10.1021/acs.jmedchem.0c00602

Experimental method

X-RAY DIFFRACTION (1.59 Å)