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- PDB-6h12: Crystal structure of TcACHE complexed to 1-(6-Oxo-1,2,3,4,6,10b-h... -

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Basic information

Entry
Database: PDB / ID: 6h12
TitleCrystal structure of TcACHE complexed to 1-(6-Oxo-1,2,3,4,6,10b-hexahydropyrido[2,1-a]isoindol-10-yl)-3-(4-(((1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)pyridin-2-yl)urea
ComponentsAcetylcholinesterase
KeywordsHYDROLASE / complex / inhibitor / alzheimer / acetylcholinesterase / multi-target-directed ligands / MTDL
Function / homology
Function and homology information


acetylcholine catabolic process in synaptic cleft / acetylcholinesterase / acetylcholinesterase activity / synaptic cleft / side of membrane / synapse / plasma membrane
Similarity search - Function
Acetylcholinesterase, fish/snake / Cholinesterase / Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase type B, active site / Carboxylesterases type-B serine active site. / Carboxylesterase, type B / Carboxylesterase family / Alpha/Beta hydrolase fold, catalytic domain / Alpha/Beta hydrolase fold ...Acetylcholinesterase, fish/snake / Cholinesterase / Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase type B, active site / Carboxylesterases type-B serine active site. / Carboxylesterase, type B / Carboxylesterase family / Alpha/Beta hydrolase fold, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-FJK / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Acetylcholinesterase
Similarity search - Component
Biological speciesTetronarce californica (Pacific electric ray)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsCoquelle, N. / Colletier, J.P.
Funding support France, 1items
OrganizationGrant numberCountry
French National Research AgencyANR-12-BS07-008-01 France
CitationJournal: Eur.J.Med.Chem. / Year: 2019
Title: Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3.
Authors: Oukoloff, K. / Coquelle, N. / Bartolini, M. / Naldi, M. / Le Guevel, R. / Bach, S. / Josselin, B. / Ruchaud, S. / Catto, M. / Pisani, L. / Denora, N. / Iacobazzi, R.M. / Silman, I. / ...Authors: Oukoloff, K. / Coquelle, N. / Bartolini, M. / Naldi, M. / Le Guevel, R. / Bach, S. / Josselin, B. / Ruchaud, S. / Catto, M. / Pisani, L. / Denora, N. / Iacobazzi, R.M. / Silman, I. / Sussman, J.L. / Buron, F. / Colletier, J.P. / Jean, L. / Routier, S. / Renard, P.Y.
History
DepositionJul 10, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 15, 2019Provider: repository / Type: Initial release
Revision 1.1May 22, 2019Group: Data collection / Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen ...pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list / struct_site / struct_site_gen
Item: _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _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: Acetylcholinesterase
B: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,46848
Polymers127,5282
Non-polymers5,94046
Water13,439746
1
A: Acetylcholinesterase
hetero molecules

B: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,46848
Polymers127,5282
Non-polymers5,94046
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_746-x+2,y-1/2,-z+3/21
Unit cell
Length a, b, c (Å)91.270, 105.090, 149.690
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein / Sugars , 2 types, 7 molecules AB

#1: Protein Acetylcholinesterase / / AChE


Mass: 63763.965 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Tetronarce californica (Pacific electric ray)
References: UniProt: P04058, acetylcholinesterase
#8: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 9 types, 787 molecules

#2: Chemical
ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C6H13NO4S / Comment: pH buffer*YM
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL / Polyethylene glycol


Mass: 150.173 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H14O4
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: SO4
#7: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C4H10O3
#9: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Cl
#10: Chemical ChemComp-FJK / 1-[4-[[1-[2-(1,2,3,4,4~{a},9~{a}-hexahydroacridin-9-ylamino)ethyl]-1,2,3-triazol-4-yl]methoxymethyl]pyridin-2-yl]-3-[(10~{b}~{R})-6-oxidanylidene-2,3,4,10~{b}-tetrahydro-1~{H}-pyrido[2,1-a]isoindol-10-yl]urea


Mass: 659.780 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C37H41N9O3
#11: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 746 / Source method: isolated from a natural source / Formula: H2O

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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: 2.72 Å3/Da / Density % sol: 54.79 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 30% PEG 200/50 mM MES pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.8726 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 8, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2.2→19.84 Å / Num. obs: 73534 / % possible obs: 99.63 % / Redundancy: 5.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.092 / Net I/σ(I): 13.6
Reflection shellResolution: 2.2→2.26 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.587 / Mean I/σ(I) obs: 2.8 / Num. unique obs: 3584 / CC1/2: 0.995 / % possible all: 99.78

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2xi4

2xi4


Resolution: 2.2→19.84 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 22.97
RfactorNum. reflection% reflection
Rfree0.2125 1997 2.72 %
Rwork0.1711 --
obs0.1722 73462 99.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.2→19.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8482 0 383 746 9611
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0099246
X-RAY DIFFRACTIONf_angle_d0.96312521
X-RAY DIFFRACTIONf_dihedral_angle_d13.4525493
X-RAY DIFFRACTIONf_chiral_restr0.0521285
X-RAY DIFFRACTIONf_plane_restr0.0061602
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.25490.23891400.20815030X-RAY DIFFRACTION100
2.2549-2.31580.28991420.19815049X-RAY DIFFRACTION100
2.3158-2.38390.23071390.19615038X-RAY DIFFRACTION100
2.3839-2.46070.24721420.18355082X-RAY DIFFRACTION100
2.4607-2.54840.23421410.18155025X-RAY DIFFRACTION100
2.5484-2.65030.24081420.17285074X-RAY DIFFRACTION100
2.6503-2.77060.21541420.16945110X-RAY DIFFRACTION100
2.7706-2.91620.23051420.16875053X-RAY DIFFRACTION100
2.9162-3.09830.21131430.17525101X-RAY DIFFRACTION100
3.0983-3.33650.21551420.16935084X-RAY DIFFRACTION100
3.3365-3.67040.19571440.16255119X-RAY DIFFRACTION100
3.6704-4.19710.17391420.14955151X-RAY DIFFRACTION100
4.1971-5.27160.1961460.15125189X-RAY DIFFRACTION100
5.2716-19.88510.20921500.18925360X-RAY DIFFRACTION99

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