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Nat Chem Biol. 2017 Jun;13(6):613-615. doi: 10.1038/nchembio.2357. Epub 2017 Mar 27.

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

Author information

1
Screening and Protein Sciences, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
2
Structural Chemistry, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
3
Department of Neurobiology, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
4
Discovery Chemistry, 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.

PMID:
28346407
DOI:
10.1038/nchembio.2357
[Indexed for MEDLINE]

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