Insights into activity and inhibition from the crystal structure of human O-GlcNAcase

• Published in: Nature chemical biology Vol. 13; no. 6; pp. 613 - 615
• Main Authors: Elsen, Nathaniel L, Patel, Sangita B, Ford, Rachael E, Hall, Dawn L, Hess, Fred, Kandula, Hari, Kornienko, Maria, Reid, John, Selnick, Harold, Shipman, Jennifer M, Sharma, Sujata, Lumb, Kevin J, Soisson, Stephen M, Klein, Daniel J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-06-2017; Nature Publishing Group
• Subjects: 631/154; 631/535/1266; 631/92/607; 631/92/72; Acetylglucosamine - metabolism; beta-N-Acetylhexosaminidases - chemistry; beta-N-Acetylhexosaminidases - metabolism; Binding Sites; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; brief-communication; Calorimetry; Catalysis; Catalytic Domain; Cell Biology; Chemistry; Chemistry/Food Science; Crystal structure; Crystallography, X-Ray; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Enzymes; Glucosamine; Humans; Hydrolase; Models, Biological; N-Acetylglucosamine; Protein Structure, Tertiary; Residues; Serine; Substrate Specificity; Threonine
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.2357

Crystallographic analysis of human O-GlcNAc hydrolase (hOGA) fragments containing the catalytic domain, including structures in complex with known inhibitors, suggests that OGA is functional as a dimer and defines opportunities for structure-based drug design.
O-GlcNAc hydrolase (OGA) catalyzes removal of βα-linked
N
-acetyl-
D
-glucosamine from serine and threonine residues. We report crystal structures of
Homo sapiens
OGA catalytic domain in apo and inhibited states, revealing a flexible dimer that displays three unique conformations and is characterized by subdomain α-helix swapping. These results identify new structural features of the substrate-binding groove adjacent to the catalytic site and open new opportunities for structural, mechanistic and drug discovery activities.