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- PDB-9ba9: O-GlcNAcase (OGA) inhibitor complex for the Treatment of Alzheime... -

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Basic information

Entry
Database: PDB / ID: 9ba9
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 / FOURIER SYNTHESIS / Resolution: 2.75 Å
AuthorsHendle, J.
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

Downloads & links

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Assembly

Deposited unit
A: Protein O-GlcNAcase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,5722
Polymers61,3331
Non-polymers2391
Water66737
1
A: Protein O-GlcNAcase
hetero molecules

A: Protein O-GlcNAcase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,1444
Polymers122,6652
Non-polymers4792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_554-y,-x,-z-1/21
Buried area7960 Å2
ΔGint-50 kcal/mol
Surface area36360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)133.261, 133.261, 114.236
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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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: 61332.586 Da / Num. of mol.: 1
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-A1AKL / N-{5-[(piperidin-1-yl)methyl]-1,3-thiazol-2-yl}acetamide


Mass: 239.337 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H17N3OS / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / 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: 4.13 Å3/Da / Density % sol: 70.25 %
Crystal growTemperature: 281 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 33% PEG 300, 100mM Hepes pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Dec 7, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 2.75→53 Å / Num. obs: 27328 / % possible obs: 100 % / Redundancy: 8.6 % / Rmerge(I) obs: 0.103 / Net I/σ(I): 4.6
Reflection shellResolution: 2.75→2.9 Å / Redundancy: 8.8 % / Rmerge(I) obs: 0.536 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 3932 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.75→30 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.911 / SU B: 11.897 / SU ML: 0.23 / Cross valid method: THROUGHOUT / ESU R: 0.355 / ESU R Free: 0.277 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26023 1371 5 %RANDOM
Rwork0.21729 ---
obs0.2194 25791 99.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 74.774 Å2
Baniso -1Baniso -2Baniso -3
1--4.99 Å2-0 Å2-0 Å2
2---4.99 Å20 Å2
3---9.97 Å2
Refinement stepCycle: 1 / Resolution: 2.75→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3633 0 16 37 3686
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0193773
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0091.9615129
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9355463
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.44523.179173
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.22515597
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0921527
X-RAY DIFFRACTIONr_chiral_restr0.0710.2551
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212911
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.75→2.821 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.381 99 -
Rwork0.36 1882 -
obs--99.85 %

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