title: Insights into activity and inhibition from the crystal structure of human O-GlcNAcase.
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.
authors.affiliation: Screening and Protein Sciences, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Nathaniel L
authors.initials: NL
authors.lastname: Elsen
authors.affiliation: Structural Chemistry, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Sangita B
authors.initials: SB
authors.lastname: Patel
authors.affiliation: Screening and Protein Sciences, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Rachael E
authors.initials: RE
authors.lastname: Ford
authors.affiliation: Screening and Protein Sciences, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Hall
authors.affiliation: Department of Neurobiology, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Hess
authors.affiliation: Screening and Protein Sciences, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Hari
authors.initials: H
authors.lastname: Kandula
authors.affiliation: Screening and Protein Sciences, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kornienko
authors.affiliation: Structural Chemistry, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: John
authors.initials: J
authors.lastname: Reid
authors.affiliation: Discovery Chemistry, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Harold
authors.initials: H
authors.lastname: Selnick
authors.affiliation: Screening and Protein Sciences, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Shipman
authors.affiliation: Screening and Protein Sciences, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Screening and Protein Sciences, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Lumb
authors.affiliation: Structural Chemistry, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Soisson
authors.affiliation: Structural Chemistry, MRL, Merck &Co., Inc., West Point, Pennsylvania, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klein
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D001665:Binding Sites; D002151:Calorimetry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D001619:beta-N-Acetylhexosaminidases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine