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Insights into activity and inhibition from the crystal structure of human O-GlcNAcase
Nathaniel L Elsen1, Sangita B Patel2, Rachael E Ford1
1Screening and Protein Sciences, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
Abstract:
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.
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