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

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Basic information

Entry
Database: PDB / ID: 6ezg
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 / choline metabolic process / acetylcholinesterase activity / synaptic cleft / side of membrane / synapse / extracellular space / 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 ...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-C6K / DI(HYDROXYETHYL)ETHER / Acetylcholinesterase
Similarity search - Component
Biological speciesTetronarce californica (Pacific electric ray)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.2 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 / Structure summary
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc / struct
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 / _struct.title
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 1.3Nov 13, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
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)123,39210
Polymers121,4732
Non-polymers1,9198
Water10,160564
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3130 Å2
ΔGint4 kcal/mol
Surface area39200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.711, 106.996, 150.494
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


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-C6K / 1-(7-chloranyl-4-methoxy-1~{H}-indol-5-yl)-3-[1-(phenylmethyl)piperidin-4-yl]propan-1-one


Mass: 410.936 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H27ClN2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 564 / Source method: isolated from a natural source / Formula: H2O
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: 3.04 Å3/Da / Density % sol: 59.53 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.8 / Details: 36% PEG 200 150mM MES pH 5.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.03 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 26, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03 Å / Relative weight: 1
ReflectionResolution: 2.2→45.42 Å / Num. obs: 73468 / % possible obs: 97 % / Redundancy: 4.51 % / Net I/σ(I): 10.8
Reflection shellResolution: 2.2→2.3 Å

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.2→45.42 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.47
RfactorNum. reflection% reflection
Rfree0.2371 3671 5 %
Rwork0.1898 --
obs0.1922 73468 96.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.2→45.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8488 0 128 564 9180
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0078876
X-RAY DIFFRACTIONf_angle_d0.99812044
X-RAY DIFFRACTIONf_dihedral_angle_d14.3163218
X-RAY DIFFRACTIONf_chiral_restr0.0421262
X-RAY DIFFRACTIONf_plane_restr0.0051562
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.22890.36951290.31722617X-RAY DIFFRACTION95
2.2289-2.25950.35421490.2982611X-RAY DIFFRACTION97
2.2595-2.29180.36381340.27812607X-RAY DIFFRACTION95
2.2918-2.3260.29081430.26682561X-RAY DIFFRACTION95
2.326-2.36230.29131270.24912633X-RAY DIFFRACTION96
2.3623-2.4010.30131390.24632660X-RAY DIFFRACTION97
2.401-2.44240.30751250.24072670X-RAY DIFFRACTION98
2.4424-2.48680.29741340.22812663X-RAY DIFFRACTION97
2.4868-2.53470.31021340.23092677X-RAY DIFFRACTION97
2.5347-2.58640.3161500.24112671X-RAY DIFFRACTION98
2.5864-2.64260.28091460.22772676X-RAY DIFFRACTION97
2.6426-2.70410.29911480.22122630X-RAY DIFFRACTION96
2.7041-2.77170.27221160.21382683X-RAY DIFFRACTION97
2.7717-2.84670.23221160.20112625X-RAY DIFFRACTION95
2.8467-2.93040.33121520.21012715X-RAY DIFFRACTION98
2.9304-3.0250.26111440.20742668X-RAY DIFFRACTION98
3.025-3.13310.29241660.21482701X-RAY DIFFRACTION98
3.1331-3.25850.25211320.20252700X-RAY DIFFRACTION98
3.2585-3.40670.21731540.19722667X-RAY DIFFRACTION97
3.4067-3.58630.21491440.17412721X-RAY DIFFRACTION97
3.5863-3.81080.21321690.16712670X-RAY DIFFRACTION97
3.8108-4.10490.1841550.14482738X-RAY DIFFRACTION99
4.1049-4.51770.1851410.13212765X-RAY DIFFRACTION99
4.5177-5.17060.15381480.1362762X-RAY DIFFRACTION98
5.1706-6.51130.20981230.15742811X-RAY DIFFRACTION98
6.5113-45.430.21011530.18572895X-RAY DIFFRACTION97

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