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- PDB-8aev: Human acetylcholinesterase in complex with N,N,N-trimethyl-2-oxo-... -

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Basic information

Entry
Database: PDB / ID: 8aev
TitleHuman acetylcholinesterase in complex with N,N,N-trimethyl-2-oxo-2-(2-(pyridin-2-ylmethylene)hydrazineyl)ethan-1-aminium
ComponentsAcetylcholinesterase
KeywordsHYDROLASE / Inhibitor / complex / zinc / acetylcholinesterase
Function / homology
Function and homology information


negative regulation of synaptic transmission, cholinergic / serine hydrolase activity / acetylcholine catabolic process in synaptic cleft / Neurotransmitter clearance / cholinesterase activity / acetylcholine catabolic process / acetylcholinesterase / amyloid precursor protein metabolic process / acetylcholine binding / osteoblast development ...negative regulation of synaptic transmission, cholinergic / serine hydrolase activity / acetylcholine catabolic process in synaptic cleft / Neurotransmitter clearance / cholinesterase activity / acetylcholine catabolic process / acetylcholinesterase / amyloid precursor protein metabolic process / acetylcholine binding / osteoblast development / acetylcholine receptor signaling pathway / acetylcholinesterase activity / Synthesis of PC / basement membrane / regulation of receptor recycling / Synthesis, secretion, and deacylation of Ghrelin / synaptic cleft / side of membrane / collagen binding / synapse assembly / laminin binding / positive regulation of protein secretion / neuromuscular junction / receptor internalization / nervous system development / positive regulation of cold-induced thermogenesis / amyloid-beta binding / retina development in camera-type eye / hydrolase activity / cell adhesion / synapse / perinuclear region of cytoplasm / cell surface / Golgi apparatus / protein homodimerization activity / extracellular space / extracellular region / nucleus / membrane / plasma membrane
Similarity search - Function
Acetylcholinesterase, tetramerisation domain / Acetylcholinesterase tetramerisation domain / : / 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-LWU / Acetylcholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.89 Å
AuthorsNachon, F. / Dias, J. / Brazzolotto, X.
Funding support France, 1items
OrganizationGrant numberCountry
French Ministry of Armed ForcesNBC-5-C-4210 France
CitationJournal: Chembiochem / Year: 2022
Title: Grid-Type Quaternary Metallosupramolecular Compounds Inhibit Human Cholinesterases through Dynamic Multivalent Interactions.
Authors: Nachon, F. / Brazzolotto, X. / Dias, J. / Courageux, C. / Drozdz, W. / Cao, X.Y. / Stefankiewicz, A.R. / Lehn, J.M.
History
DepositionJul 13, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_conn
Item: _struct_conn.pdbx_leaving_atom_flag

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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)124,97973
Polymers119,2732
Non-polymers5,70771
Water3,297183
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)211.833, 211.833, 116.634
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61
Space group name HallP61
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: -x,-y,z+1/2

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Acetylcholinesterase / AChE


Mass: 59636.277 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACHE / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P22303, acetylcholinesterase

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Sugars , 3 types, 4 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-1-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Polysaccharide N-acetyl-alpha-neuraminic acid-(2-3)-beta-D-galactopyranose


Type: oligosaccharide / Mass: 471.411 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DNeup5Aca2-3DGalpb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2112h-1b_1-5][Aad21122h-2a_2-6_5*NCC/3=O]/1-2/a3-b2WURCSPDB2Glycan 1.1.0
[][b-D-Galp]{[(3+2)][a-D-Neup5Ac]{}}LINUCSPDB-CARE

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Non-polymers , 6 types, 250 molecules

#5: Chemical ChemComp-LWU / 1-(2-(2-((6-(dihydroxymethyl)-2-phenylpyrimidin-4-yl)methylene)hydrazineyl)-2-oxoethyl)pyridin-1-ium / ~{N}'-[[6-[bis(oxidanyl)methyl]-2-phenyl-pyrimidin-4-yl]methyl]-2-pyridin-1-yl-ethanehydrazide


Mass: 366.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H20N5O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: SO4
#7: Chemical...
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 31 / Source method: obtained synthetically / Formula: Cl
#8: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn
#9: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: Mg
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 183 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 6.42 Å3/Da / Density % sol: 80.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 1.5 M LISO4, 100 MM HEPES PH7, 60 MM MGSO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.873127 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jul 21, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873127 Å / Relative weight: 1
ReflectionResolution: 2.89→46.64 Å / Num. obs: 64879 / % possible obs: 94.51 % / Redundancy: 6.6 % / Biso Wilson estimate: 76.21 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.1812 / Rpim(I) all: 0.07427 / Rrim(I) all: 0.1966 / Net I/σ(I): 8.46
Reflection shellResolution: 2.89→2.993 Å / Mean I/σ(I) obs: 0.58 / Num. unique obs: 4575 / CC1/2: 0.209

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Processing

Software
NameVersionClassification
XDSdata reduction
PHENIX1.20.1_4487refinement
XSCALEdata scaling
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6ZWE

6zwe


Resolution: 2.89→46.64 Å / SU ML: 0.4418 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 25.6113
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2072 3198 5.07 %
Rwork0.1836 59908 -
obs0.1849 63106 94.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 88.45 Å2
Refinement stepCycle: LAST / Resolution: 2.89→46.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8319 0 293 183 8795
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01028821
X-RAY DIFFRACTIONf_angle_d1.168712076
X-RAY DIFFRACTIONf_chiral_restr0.06281301
X-RAY DIFFRACTIONf_plane_restr0.01091570
X-RAY DIFFRACTIONf_dihedral_angle_d9.6051256
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.89-2.930.4063970.38281614X-RAY DIFFRACTION59.6
2.93-2.980.40761210.37092002X-RAY DIFFRACTION73.03
2.98-3.030.37821410.3552436X-RAY DIFFRACTION89.54
3.03-3.080.33341300.34312510X-RAY DIFFRACTION91.1
3.08-3.140.35241350.33032544X-RAY DIFFRACTION93.34
3.14-3.20.37631040.30852677X-RAY DIFFRACTION96.43
3.2-3.260.3321210.29862712X-RAY DIFFRACTION97.62
3.26-3.330.34871200.28892707X-RAY DIFFRACTION97.89
3.33-3.410.27911290.27462752X-RAY DIFFRACTION99
3.41-3.50.27021420.2372706X-RAY DIFFRACTION98.99
3.5-3.590.27341460.22362714X-RAY DIFFRACTION98.69
3.59-3.70.23611310.19162693X-RAY DIFFRACTION98.5
3.7-3.810.18861500.18032713X-RAY DIFFRACTION98.69
3.81-3.950.18331290.1742739X-RAY DIFFRACTION98.66
3.95-4.110.20191380.15912708X-RAY DIFFRACTION98.61
4.11-4.30.15831540.13642693X-RAY DIFFRACTION98.21
4.3-4.520.14561630.13212709X-RAY DIFFRACTION98.59
4.52-4.810.15251630.12842699X-RAY DIFFRACTION98.79
4.81-5.180.15691490.13542737X-RAY DIFFRACTION98.33
5.18-5.70.1931500.15222694X-RAY DIFFRACTION98.27
5.7-6.520.21461790.15792683X-RAY DIFFRACTION97.71
6.52-8.20.171510.15232728X-RAY DIFFRACTION97.99
8.21-46.640.16511550.14672738X-RAY DIFFRACTION96.59
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)
13.16483893097-0.9604490325670.8281104111262.90758888605-0.8811619376851.56114237111-0.0520220463707-0.091663221793-0.1166424550650.1877511845030.0550531759160.383561809751-0.04462929329320.10131322212-0.01181247284410.461720357862-0.06920487617690.1233355674290.551098626652-0.05013959713480.404562391732192.53136566388.9526575227.92455141186
23.12466748606-0.1965745494581.132668407192.93370284695-0.3426812748752.766303424560.00772259881696-0.228477811051-0.33811520975-0.1302534542260.1400622645110.875248313602-0.114694656839-0.41583120829-0.1070934132840.43202491493-0.0471345841356-0.02107890576610.564186671426-0.04635479441620.731881019848156.531191782123.111957976-25.5268188555
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Label seq-ID: 1

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-ID
11chain AAA - I5 - 606
22chain BBJ - M5 - 602

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