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- PDB-6pm9: Crystal structure of the core catalytic domain of human O-GlcNAca... -

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Basic information

Entry
Database: PDB / ID: 6pm9
TitleCrystal structure of the core catalytic domain of human O-GlcNAcase bound to MK-8719
Components
  • O-GlcNAcase TIM-barrel domain
  • O-GlcNAcase stalk domain
KeywordsHYDROLASE / O-GLCNACASE / GH84 / INHIBITOR
Function / homology
Function and homology information


hyalurononglucosaminidase activity / glycoprotein metabolic process / N-acetylglucosamine metabolic process / glycoprotein catabolic process / protein O-GlcNAcase / : / : / [protein]-3-O-(N-acetyl-D-glucosaminyl)-L-serine/L-threonine O-N-acetyl-alpha-D-glucosaminase activity / protein O-linked glycosylation / protein deglycosylation ...hyalurononglucosaminidase activity / glycoprotein metabolic process / N-acetylglucosamine metabolic process / glycoprotein catabolic process / protein O-GlcNAcase / : / : / [protein]-3-O-(N-acetyl-D-glucosaminyl)-L-serine/L-threonine O-N-acetyl-alpha-D-glucosaminase activity / protein O-linked glycosylation / protein deglycosylation / beta-N-acetylglucosaminidase activity / identical protein binding / membrane / nucleus / cytosol
Similarity search - Function
Glycosyl hydrolases family 84 (GH84) domain profile. / Beta-N-acetylglucosaminidase / beta-N-acetylglucosaminidase / Acyl-CoA N-acyltransferase / Glycosidases / Glycoside hydrolase superfamily / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-OQ1 / Protein O-GlcNAcase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.86 Å
AuthorsKlein, D.J. / Selnick, H.G. / Duffy, J.L. / McEachern, E.J.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies.
Authors: Selnick, H.G. / Hess, J.F. / Tang, C. / Liu, K. / Schachter, J.B. / Ballard, J.E. / Marcus, J. / Klein, D.J. / Wang, X. / Pearson, M. / Savage, M.J. / Kaul, R. / Li, T.S. / Vocadlo, D.J. / ...Authors: Selnick, H.G. / Hess, J.F. / Tang, C. / Liu, K. / Schachter, J.B. / Ballard, J.E. / Marcus, J. / Klein, D.J. / Wang, X. / Pearson, M. / Savage, M.J. / Kaul, R. / Li, T.S. / Vocadlo, D.J. / Zhou, Y. / Zhu, Y. / Mu, C. / Wang, Y. / Wei, Z. / Bai, C. / Duffy, J.L. / McEachern, E.J.
History
DepositionJul 1, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 18, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: O-GlcNAcase TIM-barrel domain
B: O-GlcNAcase TIM-barrel domain
C: O-GlcNAcase TIM-barrel domain
D: O-GlcNAcase TIM-barrel domain
E: O-GlcNAcase stalk domain
F: O-GlcNAcase stalk domain
G: O-GlcNAcase stalk domain
H: O-GlcNAcase stalk domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)250,69112
Polymers249,6188
Non-polymers1,0734
Water63135
1
A: O-GlcNAcase TIM-barrel domain
B: O-GlcNAcase TIM-barrel domain
F: O-GlcNAcase stalk domain
G: O-GlcNAcase stalk domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,3466
Polymers124,8094
Non-polymers5372
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10910 Å2
ΔGint-91 kcal/mol
Surface area35920 Å2
MethodPISA
2
C: O-GlcNAcase TIM-barrel domain
D: O-GlcNAcase TIM-barrel domain
E: O-GlcNAcase stalk domain
H: O-GlcNAcase stalk domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,3466
Polymers124,8094
Non-polymers5372
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11490 Å2
ΔGint-81 kcal/mol
Surface area35740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.920, 91.460, 94.610
Angle α, β, γ (deg.)77.270, 62.610, 62.860
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
O-GlcNAcase TIM-barrel domain / OGA / Beta-N-acetylglucosaminidase / Beta-N-acetylhexosaminidase / Beta-hexosaminidase / Meningioma- ...OGA / Beta-N-acetylglucosaminidase / Beta-N-acetylhexosaminidase / Beta-hexosaminidase / Meningioma-expressed antigen 5 / N-acetyl-beta-D-glucosaminidase / N-acetyl-beta-glucosaminidase / Nuclear cytoplasmic O-GlcNAcase and acetyltransferase / NCOAT


Mass: 43642.105 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MGEA5, HEXC, KIAA0679, MEA5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O60502, protein O-GlcNAcase
#2: Protein
O-GlcNAcase stalk domain / OGA / Beta-N-acetylglucosaminidase / Beta-N-acetylhexosaminidase / Beta-hexosaminidase / Meningioma- ...OGA / Beta-N-acetylglucosaminidase / Beta-N-acetylhexosaminidase / Beta-hexosaminidase / Meningioma-expressed antigen 5 / N-acetyl-beta-D-glucosaminidase / N-acetyl-beta-glucosaminidase / Nuclear cytoplasmic O-GlcNAcase and acetyltransferase / NCOAT


Mass: 18762.463 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MGEA5, HEXC, KIAA0679, MEA5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O60502, protein O-GlcNAcase
#3: Chemical
ChemComp-OQ1 / (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol


Mass: 268.281 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H14F2N2O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 35 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.12 Å3/Da / Density % sol: 60.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.2 M K-Na-tartrate tetrahydrate, 20% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 23, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.86→70.484 Å / Num. obs: 52089 / % possible obs: 95.1 % / Redundancy: 1.8 % / Biso Wilson estimate: 79.71 Å2 / Net I/σ(I): 7.2
Reflection shellResolution: 2.86→2.913 Å / Num. unique obs: 2510

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Processing

Software
NameVersionClassification
Aimlessdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.86→40.69 Å / Cor.coef. Fo:Fc: 0.875 / Cor.coef. Fo:Fc free: 0.806 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 4.505 / SU Rfree Blow DPI: 0.439
RfactorNum. reflection% reflectionSelection details
Rfree0.309 2706 5.2 %RANDOM
Rwork0.239 ---
obs0.243 52075 95.1 %-
Displacement parametersBiso max: 136.43 Å2 / Biso mean: 60.57 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--3.2021 Å2-6.917 Å212.1011 Å2
2--6.3583 Å210.7345 Å2
3----3.1562 Å2
Refine analyzeLuzzati coordinate error obs: 0.46 Å
Refinement stepCycle: final / Resolution: 2.86→40.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13813 0 68 35 13916
Biso mean--51.06 36.16 -
Num. residues----1688
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4909SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes2368HARMONIC8
X-RAY DIFFRACTIONt_it14241HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1766SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact16692SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d14241HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg19261HARMONIC21.18
X-RAY DIFFRACTIONt_omega_torsion1.92
X-RAY DIFFRACTIONt_other_torsion22.29
LS refinement shellResolution: 2.86→2.89 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2991 60 5.76 %
Rwork0.2669 982 -
all0.2688 1042 -
obs--86.04 %

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