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

被引：70

作者：

Elsen, Nathaniel L. ^{[1
,5
]}

Patel, Sangita B. ^{[2
]}

Ford, Rachael E. ^{[1
]}

Hall, Dawn L. ^{[1
]}

Hess, Fred ^{[3
]}

Kandula, Hari ^{[1
]}

Kornienko, Maria ^{[1
]}

Reid, John ^{[2
]}

Selnick, Harold ^{[4
]}

Shipman, Jennifer M. ^{[1
]}

Sharma, Sujata ^{[1
]}

Lumb, Kevin J. ^{[1
,6
]}

Soisson, Stephen M. ^{[2
]}

Klein, Daniel J. ^{[2
]}

机构：

[1] Merck & Co Inc, MRL, Screening & Prot Sci, West Point, PA USA

[2] Merck & Co Inc, MRL, Struct Chem, West Point, PA USA

[3] Merck & Co Inc, MRL, Dept Neurobiol, West Point, PA USA

[4] Merck & Co Inc, MRL, Discovery Chem, West Point, PA USA

[5] AbbVie Inc, High Throughput Screening, N Chicago, IL USA

[6] Janssen R&D LLC, Discovery Sci, Lead Discovery, Spring House, PA USA

来源：

NATURE CHEMICAL BIOLOGY | 2017年 / 13卷 / 06期

关键词：

BETA-N-ACETYLGLUCOSAMINIDASE; CYTOSOLIC PROTEINS; MECHANISM; GLYCOSYLATION; TRANSFERASE; NUCLEAR; PEPTIDE; CLONING; TAU;

D O I：

10.1038/nchembio.2357

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

O-GlcNAc hydrolase (OGA) catalyzes removal of beta-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 alpha-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.

引用

页码：613 / U205

页数：5

共 32 条

[1] DIRECT PHASE DETERMINATION BY ENTROPY MAXIMIZATION AND LIKELIHOOD RANKING - STATUS-REPORT AND PERSPECTIVES [J].

BRICOGNE, G .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 1993, 49 :37-60

[2] Characterization of β-N-acetylglucosaminidase cleavage by caspase-3 during apoptosis [J].

Butkinaree, Chutikarn ;

Cheung, Win D. ;

Park, Sungjin ;

Park, Kyoungsook ;

Barber, Megan ;

Hart, Gerald W. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (35) :23557-23566

[3] The Carbohydrate-Active EnZymes database (CAZy): an expert resource for Glycogenomics [J].

Cantarel, Brandi L. ;

Coutinho, Pedro M. ;

Rancurel, Corinne ;

Bernard, Thomas ;

Lombard, Vincent ;

Henrissat, Bernard .

NUCLEIC ACIDS RESEARCH, 2009, 37 :D233-D238

[4] Identification of Asp174 and Asp175 as the key catalytic residues of human O-GlcNAcase by functional analysis of site-directed mutants [J].

Çetinbas, N ;

Macauley, MS ;

Stubbs, KA ;

Drapala, R ;

Vocadlo, DJ .

BIOCHEMISTRY, 2006, 45 (11) :3835-3844

[5]

CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099

[6] Discovery of Selective Small-Molecule Activators of a Bacterial Glycoside Hydrolase [J].

Darby, John F. ;

Landstrom, Jens ;

Roth, Christian ;

He, Yuan ;

Davies, Gideon J. ;

Hubbard, Roderick E. .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2014, 53 (49) :13419-13423

[7] Structure and mechanism of a bacterial β-glucosaminidase having O-GlcNAcase activity [J].

Dennis, RJ ;

Taylor, EJ ;

Macauley, MS ;

Stubbs, KA ;

Turkenburg, JP ;

Hart, SJ ;

Black, GN ;

Vocadlo, DJ ;

Davies, GJ .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2006, 13 (04) :365-371

[8] Features and development of Coot [J].

Emsley, P. ;

Lohkamp, B. ;

Scott, W. G. ;

Cowtan, K. .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 2010, 66 :486-501

[9] Dynamic O-glycosylation of nuclear and cytosolic proteins -: Cloning and characterization of a neutral, cytosolic β-N-acetylglucosaminidase from human brain [J].

Gao, Y ;

Wells, L ;

Comer, FI ;

Parker, GJ ;

Hart, GW .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (13) :9838-9845

[10] A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome [J].

Keembiyehetty, Chithra N. ;

Krzeslak, Anna ;

Love, Dona C. ;

Hanover, John A. .

JOURNAL OF CELL SCIENCE, 2011, 124 (16) :2851-2860

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