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- PDB-9ba8: O-GlcNAcase (OGA) inhibitor complex for the Treatment of Alzheime... -

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Basic information

Entry
Database: PDB / ID: 9ba8
TitleO-GlcNAcase (OGA) inhibitor complex for the Treatment of Alzheimer's Disease
ComponentsProtein O-GlcNAcase
KeywordsHYDROLASE / Inhibitor / Complex / O-GlcNAcase
Function / homology
Function and homology information


glycoprotein metabolic process / hyalurononglucosaminidase activity / N-acetylglucosamine metabolic process / protein deglycosylation / protein O-GlcNAcase / [protein]-3-O-(N-acetyl-D-glucosaminyl)-L-serine/L-threonine O-N-acetyl-alpha-D-glucosaminase activity / glycoprotein catabolic process / protein O-linked glycosylation / beta-N-acetylglucosaminidase activity / identical protein binding ...glycoprotein metabolic process / hyalurononglucosaminidase activity / N-acetylglucosamine metabolic process / protein deglycosylation / protein O-GlcNAcase / [protein]-3-O-(N-acetyl-D-glucosaminyl)-L-serine/L-threonine O-N-acetyl-alpha-D-glucosaminase activity / glycoprotein catabolic process / protein O-linked glycosylation / beta-N-acetylglucosaminidase activity / identical protein binding / nucleus / membrane / cytosol
Similarity search - Function
Beta-N-acetylglucosaminidase / beta-N-acetylglucosaminidase / Glycosyl hydrolases family 84 (GH84) domain profile. / : / Acyl-CoA N-acyltransferase / Glycoside hydrolase superfamily
Similarity search - Domain/homology
: / Protein O-GlcNAcase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.54 Å
AuthorsHendle, J. / Romero, R.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Alzheimers Dement (N Y) / Year: 2024
Title: Discovery and clinical translation of ceperognastat, an O-GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease.
Authors: Kielbasa, W. / Goldsmith, P. / Donnelly, K.B. / Nuthall, H.N. / Shcherbinin, S. / Fleisher, A.S. / Hendle, J. / DuBois, S.L. / Lowe, S.L. / Zhang, F.F. / Woerly, E.M. / Dreyfus, N.J. / ...Authors: Kielbasa, W. / Goldsmith, P. / Donnelly, K.B. / Nuthall, H.N. / Shcherbinin, S. / Fleisher, A.S. / Hendle, J. / DuBois, S.L. / Lowe, S.L. / Zhang, F.F. / Woerly, E.M. / Dreyfus, N.J. / Evans, D. / Gilmore, J. / Mancini, M. / Constantinescu, C.C. / Gunn, R.N. / Russell, D.S. / Collins, E.C. / Brys, M. / Hutton, M.L. / Mergott, D.J.
History
DepositionApr 3, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 15, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein O-GlcNAcase
B: Protein O-GlcNAcase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,5284
Polymers114,7612
Non-polymers7672
Water1,874104
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6270 Å2
ΔGint-46 kcal/mol
Surface area35780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)132.096, 134.580, 61.000
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Protein O-GlcNAcase / 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: 57380.328 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: OGA, HEXC, KIAA0679, MEA5, MGEA5 / Production host: Escherichia coli (E. coli) / References: UniProt: O60502, protein O-GlcNAcase
#2: Chemical ChemComp-A1AKM / N-[4-fluoro-5-({(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]piperidin-1-yl}methyl)-1,3-thiazol-2-yl]acetamide


Mass: 383.441 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H22FN5O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 104 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.36 Å3/Da / Density % sol: 47.93 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 15% PEG 3350, 200mM Magnesium Chloride, 100mM Hepes pH 7.0, 5% DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.92819 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 22, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 2.54→66 Å / Num. obs: 36205 / % possible obs: 100 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 6.8
Reflection shellResolution: 2.54→2.65 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.876 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 5184 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
autoPROCdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.54→35.38 Å / Cor.coef. Fo:Fc: 0.9275 / Cor.coef. Fo:Fc free: 0.9201 / SU R Cruickshank DPI: 0.541 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.529 / SU Rfree Blow DPI: 0.261 / SU Rfree Cruickshank DPI: 0.265
RfactorNum. reflection% reflectionSelection details
Rfree0.2312 1782 4.93 %RANDOM
Rwork0.1997 ---
obs0.2012 36174 98.68 %-
Displacement parametersBiso mean: 61.35 Å2
Baniso -1Baniso -2Baniso -3
1-3.1423 Å20 Å20 Å2
2--5.1191 Å20 Å2
3----8.2614 Å2
Refine analyzeLuzzati coordinate error obs: 0.329 Å
Refinement stepCycle: 1 / Resolution: 2.54→35.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7218 0 52 104 7374
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.017517HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0110253HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2533SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes166HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1082HARMONIC5
X-RAY DIFFRACTIONt_it7517HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.15
X-RAY DIFFRACTIONt_other_torsion17.71
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion938SEMIHARMONIC5
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_contact8705SEMIHARMONIC4
LS refinement shellResolution: 2.54→2.61 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.2966 111 4.48 %
Rwork0.2101 2365 -
all0.2141 2476 -
obs--84.63 %

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