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- PDB-7ais: Crystal structure of Torpedo Californica acetylcholinesterase in ... -

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Basic information

Entry
Database: PDB / ID: 7ais
TitleCrystal structure of Torpedo Californica acetylcholinesterase in complex with 6-[(3-Chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]-N-(4-hydroxy-3-methoxybenzyl)hexanamide
ComponentsAcetylcholinesterase
KeywordsHYDROLASE / Torpedo Californica acetylcholinesterase / AD / alzheimer disease
Function / homology
Function and homology information


acetylcholine catabolic process in synaptic cleft / choline metabolic process / acetylcholinesterase / acetylcholinesterase activity / synaptic cleft / side of membrane / synapse / extracellular space / plasma membrane
Similarity search - Function
Acetylcholinesterase, fish/snake / : / Cholinesterase / Carboxylesterase type B, active site / Carboxylesterases type-B serine active site. / Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase, type B / Carboxylesterase family / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Chem-8UH / DI(HYDROXYETHYL)ETHER / Acetylcholinesterase
Similarity search - Component
Biological speciesTetronarce californica (Pacific electric ray)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsCoquelle, N. / Colletier, J.P.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice.
Authors: Viayna, E. / Coquelle, N. / Cieslikiewicz-Bouet, M. / Cisternas, P. / Oliva, C.A. / Sanchez-Lopez, E. / Ettcheto, M. / Bartolini, M. / De Simone, A. / Ricchini, M. / Rendina, M. / Pons, M. / ...Authors: Viayna, E. / Coquelle, N. / Cieslikiewicz-Bouet, M. / Cisternas, P. / Oliva, C.A. / Sanchez-Lopez, E. / Ettcheto, M. / Bartolini, M. / De Simone, A. / Ricchini, M. / Rendina, M. / Pons, M. / Firuzi, O. / Perez, B. / Saso, L. / Andrisano, V. / Nachon, F. / Brazzolotto, X. / Garcia, M.L. / Camins, A. / Silman, I. / Jean, L. / Inestrosa, N.C. / Colletier, J.P. / Renard, P.Y. / Munoz-Torrero, D.
History
DepositionSep 28, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1May 4, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)134,50514
Polymers131,9412
Non-polymers2,56312
Water19,2041066
1
A: Acetylcholinesterase
hetero molecules

B: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,50514
Polymers131,9412
Non-polymers2,56312
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_755-x+2,y+1/2,-z+1/21
Buried area3880 Å2
ΔGint-2 kcal/mol
Surface area39250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.899, 106.755, 150.707
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 65970.711 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Tetronarce californica (Pacific electric ray)
References: UniProt: P04058, acetylcholinesterase
#3: 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


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: obtained synthetically / 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 , 4 types, 1073 molecules

#2: Chemical ChemComp-8UH / 6-[(3-Chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]-N-(4-hydroxy-3-methoxybenzyl)hexanamide


Mass: 534.089 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H36ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1066 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.8 Å3/Da / Density % sol: 56.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 28% PEG 200 50 mM MES / PH range: 5.8-6.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.9801 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Feb 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9801 Å / Relative weight: 1
ReflectionResolution: 1.75→46.2 Å / Num. obs: 149119 / % possible obs: 99.6 % / Redundancy: 5.5 % / Biso Wilson estimate: 35 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.069 / Net I/σ(I): 13.2
Reflection shellResolution: 1.75→1.84 Å / Redundancy: 5.5 % / Rmerge(I) obs: 0.996 / Num. unique obs: 13240 / CC1/2: 0.776 / % possible all: 99.5

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2xi4

2xi4


Resolution: 1.75→46.157 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2085 7457 5 %
Rwork0.1874 141662 -
obs0.1884 149119 99.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 97 Å2 / Biso mean: 32.7605 Å2 / Biso min: 17.56 Å2
Refinement stepCycle: final / Resolution: 1.75→46.157 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8480 0 169 1066 9715
Biso mean--43.93 41.63 -
Num. residues----1064
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0089041
X-RAY DIFFRACTIONf_angle_d1.06112299
X-RAY DIFFRACTIONf_chiral_restr0.1281290
X-RAY DIFFRACTIONf_plane_restr0.0061595
X-RAY DIFFRACTIONf_dihedral_angle_d12.5445366
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.75-1.76990.34182460.32834653100
1.7699-1.79070.34022570.32224660100
1.7907-1.81260.3562250.29884704100
1.8126-1.83550.32082560.27844683100
1.8355-1.85970.26372590.25754657100
1.8597-1.88510.26662180.2474714100
1.8851-1.91210.25492350.23684696100
1.9121-1.94060.24652570.2214641100
1.9406-1.97090.25752560.21774666100
1.9709-2.00320.25782320.21664724100
2.0032-2.03780.22582310.21114704100
2.0378-2.07480.22992770.19744643100
2.0748-2.11470.21152260.19814693100
2.1147-2.15790.22682510.19414694100
2.1579-2.20480.21652650.19714680100
2.2048-2.25610.20252530.19654702100
2.2561-2.31250.24112470.18884726100
2.3125-2.37510.24592520.19054690100
2.3751-2.44490.22332330.18374722100
2.4449-2.52390.24242520.18234728100
2.5239-2.6140.21972440.19234727100
2.614-2.71870.22312580.18614737100
2.7187-2.84240.19052540.18974704100
2.8424-2.99220.22912590.18444756100
2.9922-3.17970.18542610.18344735100
3.1797-3.42510.2082610.1844755100
3.4251-3.76970.15932440.16364774100
3.7697-4.31480.17682630.15094796100
4.3148-5.43480.16332280.1483487499
5.4348-46.1570.19572570.1975502499

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