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- PDB-6ezh: Torpedo californica AChE in complex with indolic multi-target dir... -

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Basic information

Entry
Database: PDB / ID: 6ezh
TitleTorpedo californica AChE in complex with indolic multi-target directed ligand
ComponentsAcetylcholinesterase
KeywordsHYDROLASE / Acetylcholinesterase / Multi-target inhibitor / Alzheimer desease
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-C6H / Acetylcholinesterase
Similarity search - Component
Biological speciesTetronarce californica (Pacific electric ray)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.6 Å
AuthorsSantoni, G. / Lalut, J. / Karila, D. / Lecoutey, C. / Davis, A. / Nachon, F. / Sillman, I. / Sussman, J. / Weik, M. / Maurice, T. ...Santoni, G. / Lalut, J. / Karila, D. / Lecoutey, C. / Davis, A. / Nachon, F. / Sillman, I. / Sussman, J. / Weik, M. / Maurice, T. / Dallemagne, P. / Rochais, C.
CitationJournal: Eur J Med Chem / Year: 2018
Title: Novel multitarget-directed ligands targeting acetylcholinesterase and sigma1receptors as lead compounds for treatment of Alzheimer's disease: Synthesis, evaluation, and structural ...Title: Novel multitarget-directed ligands targeting acetylcholinesterase and sigma1receptors as lead compounds for treatment of Alzheimer's disease: Synthesis, evaluation, and structural characterization of their complexes with acetylcholinesterase.
Authors: Lalut, J. / Santoni, G. / Karila, D. / Lecoutey, C. / Davis, A. / Nachon, F. / Silman, I. / Sussman, J. / Weik, M. / Maurice, T. / Dallemagne, P. / Rochais, C.
History
DepositionNov 15, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 21, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 28, 2018Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
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

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Assembly

Deposited unit
A: Acetylcholinesterase
B: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,1928
Polymers121,4732
Non-polymers1,7196
Water9,908550
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2630 Å2
ΔGint1 kcal/mol
Surface area38920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.440, 106.740, 150.750
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Acetylcholinesterase / / AChE


Mass: 60736.516 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Tetronarce californica (Pacific electric ray)
References: UniProt: P04058, acetylcholinesterase
#2: 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.: 4
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
#3: Chemical ChemComp-C6H / 1-(7-chloranyl-4-methoxy-1~{H}-indol-5-yl)-3-[1-(cyclohexylmethyl)piperidin-4-yl]propan-1-one / MR28926


Mass: 416.984 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H33ClN2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 550 / 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: 3.03 Å3/Da / Density % sol: 59.38 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 36% PEG 200 150mM MES pH 5.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.939 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 28, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.939 Å / Relative weight: 1
ReflectionResolution: 2.6→46.09 Å / Num. obs: 45936 / % possible obs: 99.72 % / Redundancy: 4.49 % / Net I/σ(I): 8.43
Reflection shellResolution: 2.6→2.67 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0107refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementStarting model: 1ea5

1ea5


Resolution: 2.6→46.09 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.901 / Cross valid method: THROUGHOUT / ESU R: 0.632 / ESU R Free: 0.326 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27315 1379 3 %RANDOM
Rwork0.22192 ---
obs0.22342 44557 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 13.113 Å2
Baniso -1Baniso -2Baniso -3
1--1.61 Å20 Å2-0 Å2
2--5.28 Å2-0 Å2
3----3.67 Å2
Refinement stepCycle: 1 / Resolution: 2.6→46.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8488 0 114 570 9172
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0198876
X-RAY DIFFRACTIONr_bond_other_d00.028115
X-RAY DIFFRACTIONr_angle_refined_deg1.2711.95712059
X-RAY DIFFRACTIONr_angle_other_deg3.976318693
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.20451064
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.94223.995423
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.545151415
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3661549
X-RAY DIFFRACTIONr_chiral_restr0.0850.21257
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02110081
X-RAY DIFFRACTIONr_gen_planes_other0.0080.022148
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_it3.1261.2674259
X-RAY DIFFRACTIONr_mcbond_other3.1191.2674258
X-RAY DIFFRACTIONr_mcangle_it4.1621.8815322
X-RAY DIFFRACTIONr_mcangle_other4.1651.8825323
X-RAY DIFFRACTIONr_scbond_it4.7791.4024617
X-RAY DIFFRACTIONr_scbond_other4.7541.3824554
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.8431.9846650
X-RAY DIFFRACTIONr_long_range_B_refined6.0310.50210880
X-RAY DIFFRACTIONr_long_range_B_other5.92310.21110602
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.6→2.668 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.363 100 -
Rwork0.294 3229 -
obs--99.85 %

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