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- PDB-2xpk: Cell-penetrant, nanomolar O-GlcNAcase inhibitors selective agains... -

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Basic information

Entry
Database: PDB / ID: 2xpk
TitleCell-penetrant, nanomolar O-GlcNAcase inhibitors selective against lysosomal hexosaminidases
ComponentsO-GLCNACASE NAGJ
KeywordsHYDROLASE / SIGNALLING
Function / homology
Function and homology information


protein O-GlcNAcase / : / : / [protein]-3-O-(N-acetyl-D-glucosaminyl)-L-serine/L-threonine O-N-acetyl-alpha-D-glucosaminase activity / protein deglycosylation / polysaccharide catabolic process / beta-N-acetylglucosaminidase activity / carbohydrate binding / carbohydrate metabolic process
Similarity search - Function
: / Hyaluronidase post-catalytic domain-like / Hyaluronidase post-catalytic domain-like / Cellulosome anchoring protein, cohesin domain / Cohesin domain / Glycosyl hydrolases family 84 (GH84) domain profile. / Beta-N-acetylglucosaminidase / beta-N-acetylglucosaminidase / Chitobiase/beta-hexosaminidase domain 2-like / Chitobiase; domain 2 ...: / Hyaluronidase post-catalytic domain-like / Hyaluronidase post-catalytic domain-like / Cellulosome anchoring protein, cohesin domain / Cohesin domain / Glycosyl hydrolases family 84 (GH84) domain profile. / Beta-N-acetylglucosaminidase / beta-N-acetylglucosaminidase / Chitobiase/beta-hexosaminidase domain 2-like / Chitobiase; domain 2 / Beta-hexosaminidase, bacterial type, N-terminal / Glycosyl hydrolase family 20, domain 2 / Beta-hexosaminidase-like, domain 2 / CBM2/CBM3, carbohydrate-binding domain superfamily / F5/8 type C domain / Coagulation factor 5/8 C-terminal domain / Fibronectin type III domain / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Galactose-binding-like domain superfamily / Fibronectin type III / Fibronectin type III superfamily / Glycosidases / Glycoside hydrolase superfamily / TIM Barrel / Alpha-Beta Barrel / Immunoglobulin-like fold / Up-down Bundle / 2-Layer Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-Z0M / O-GlcNAcase NagJ
Similarity search - Component
Biological speciesCLOSTRIDIUM PERFRINGENS (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / DIRECT METHODS / Resolution: 2.4 Å
AuthorsDorfmueller, H.C. / Borodkin, V.S. / Schimpl, M. / Zheng, X. / Kime, R. / Read, K.D. / van Aalten, D.M.F.
CitationJournal: Chem.Biol / Year: 2010
Title: Cell-Penetrant, Nanomolar O-Glcnacase Inhibitors Selective Against Lysosomal Hexosaminidases.
Authors: Dorfmueller, H.C. / Borodkin, V.S. / Schimpl, M. / Zheng, X. / Kime, R. / Read, K.D. / Van Aalten, D.M.F.
History
DepositionAug 26, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 16, 2011Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AC" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AC" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 8-STRANDED BARREL THIS IS REPRESENTED BY A 9-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. THE SHEETS PRESENTED AS "BC" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 8-STRANDED BARREL THIS IS REPRESENTED BY A 9-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: O-GLCNACASE NAGJ
B: O-GLCNACASE NAGJ
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,1704
Polymers133,3872
Non-polymers7832
Water8,287460
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2600 Å2
ΔGint-10.9 kcal/mol
Surface area45510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)130.145, 144.970, 153.061
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number24
Space group name H-MI212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A41 - 641
2114B41 - 641

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Components

#1: Protein O-GLCNACASE NAGJ / BETA-HEXOSAMINIDASE / N-ACETYL-BETA-GLUCOSAMINIDASE / BETA-N- ACETYLHEXOSAMINIDASE / HEXOSAMINIDASE ...BETA-HEXOSAMINIDASE / N-ACETYL-BETA-GLUCOSAMINIDASE / BETA-N- ACETYLHEXOSAMINIDASE / HEXOSAMINIDASE B / GH84 / CPOGA


Mass: 66693.703 Da / Num. of mol.: 2 / Fragment: RESIDUES 31-624 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) CLOSTRIDIUM PERFRINGENS (bacteria) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)PLYSS / References: UniProt: Q0TR53, beta-N-acetylhexosaminidase
#2: Chemical ChemComp-Z0M / N-[(5R,6R,7R,8S)-6,7-DIHYDROXY-5-(HYDROXYMETHYL)-2-(2-PHENYLETHYL)-5,6,7,8-TETRAHYDROIMIDAZO[1,2-A]PYRIDIN-8-YL]-3-SULFANYLPROPANAMIDE / GLCNACSTATIN F


Mass: 391.485 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H25N3O4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 460 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, VAL 331 TO CYS ENGINEERED RESIDUE IN CHAIN B, VAL 331 TO CYS
Sequence detailsCPNAGJ WAS CLONED FROM GENOMIC DNA. ASN388ASP WAS IDENTIFIED BY SEQUENCING.

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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: 2.71 Å3/Da / Density % sol: 54.55 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: BM14 / Wavelength: 0.934
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 2.4→20 Å / Num. obs: 53607 / % possible obs: 95.9 % / Observed criterion σ(I): 2 / Redundancy: 4 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 14.7
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.61 / Mean I/σ(I) obs: 2.3 / % possible all: 88.6

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: DIRECT METHODS
Starting model: PDB ENTRY 2J62

2j62


Resolution: 2.4→20.02 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.908 / SU B: 17.326 / SU ML: 0.18 / Cross valid method: THROUGHOUT / ESU R: 0.395 / ESU R Free: 0.251 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED. ATOM RECORD CONTAINS SUM OF TLS AND RESIDUAL B FACTORS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24231 537 1 %RANDOM
Rwork0.19561 ---
obs0.19608 53038 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.113 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å20 Å2-0 Å2
2---0.06 Å20 Å2
3---0.1 Å2
Refinement stepCycle: LAST / Resolution: 2.4→20.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9255 0 54 460 9769
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0229508
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3381.95812914
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.01851169
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.23425.951489
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.694151598
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.4891536
X-RAY DIFFRACTIONr_chiral_restr0.0960.21405
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0217376
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_it0.7681.55833
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.4629403
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.95333675
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.2844.53510
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
Refine LS restraints NCS

Ens-ID: 1 / Number: 4608 / Refine-ID: X-RAY DIFFRACTION

Dom-IDAuth asym-IDTypeRms dev position (Å)Weight position
1Amedium positional0.310.5
2Bmedium positional0.310.5
1Amedium thermal0.972
2Bmedium thermal0.972
LS refinement shellResolution: 2.405→2.467 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.249 28 -
Rwork0.272 3178 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.38150.24160.10430.5619-0.06160.08830.02540.0618-0.0563-0.07220.0339-0.00370.04010.0434-0.05930.11480.0203-0.00140.0613-0.02520.10357.12043.18211.4968
21.00290.0965-0.15020.0880.09480.2047-0.0508-0.15740.035-0.01250.04040.03280.0070.08920.01040.09180.0336-0.00150.1274-0.00680.061431.590937.84536.706
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A40 - 624
2X-RAY DIFFRACTION1A1625
3X-RAY DIFFRACTION2B40 - 624
4X-RAY DIFFRACTION2B1625

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