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

Nathaniel L Elsen; Sangita B Patel; Rachael E Ford; Dawn L Hall; Fred Hess; Hari Kandula; Maria Kornienko; John Reid; Harold Selnick; Jennifer M Shipman; Sujata Sharma; Kevin J Lumb; Stephen M Soisson; Daniel J Klein

doi:10.1038/nchembio.2357

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

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

Affiliations

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.

PMID: 28346407
DOI: 10.1038/nchembio.2357

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetylglucosamine / metabolism
Binding Sites
Calorimetry
Catalytic Domain
Crystallography, X-Ray
Enzyme Activation / drug effects
Enzyme Inhibitors / pharmacology
Humans
Models, Biological*
Protein Structure, Tertiary
Substrate Specificity
beta-N-Acetylhexosaminidases / chemistry*
beta-N-Acetylhexosaminidases / metabolism*

Substances

Enzyme Inhibitors
hexosaminidase C
beta-N-Acetylhexosaminidases
Acetylglucosamine