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- PDB-7e3h: Crystal structure of human acetylcholinesterase in complex with d... -

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Basic information

Entry
Database: PDB / ID: 7e3h
TitleCrystal structure of human acetylcholinesterase in complex with donepezil
ComponentsAcetylcholinesterase
KeywordsHYDROLASE / Human acetylcholinesterase / hAChE / Alzheimer's disease
Function / homology
Function and homology information


negative regulation of synaptic transmission, cholinergic / Neurotransmitter clearance / acetylcholine catabolic process in synaptic cleft / cholinesterase activity / serine hydrolase activity / acetylcholine catabolic process / acetylcholine binding / amyloid precursor protein metabolic process / acetylcholinesterase / acetylcholine receptor signaling pathway ...negative regulation of synaptic transmission, cholinergic / Neurotransmitter clearance / acetylcholine catabolic process in synaptic cleft / cholinesterase activity / serine hydrolase activity / acetylcholine catabolic process / acetylcholine binding / amyloid precursor protein metabolic process / acetylcholinesterase / acetylcholine receptor signaling pathway / osteoblast development / acetylcholinesterase activity / choline metabolic process / Synthesis of PC / basement membrane / regulation of receptor recycling / Synthesis, secretion, and deacylation of Ghrelin / side of membrane / synaptic cleft / laminin binding / synapse assembly / collagen binding / positive regulation of protein secretion / neuromuscular junction / receptor internalization / : / retina development in camera-type eye / nervous system development / positive regulation of cold-induced thermogenesis / amyloid-beta binding / hydrolase activity / cell adhesion / synapse / perinuclear region of cytoplasm / Golgi apparatus / cell surface / protein homodimerization activity / extracellular space / extracellular region / membrane / nucleus / plasma membrane
Similarity search - Function
Acetylcholinesterase, tetramerisation domain / Acetylcholinesterase tetramerisation domain / 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
Similarity search - Domain/homology
Chem-E20 / Acetylcholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsDileep, K.V. / Ihara, K. / Mishima-Tsumagari, C. / Kukimoto-Niino, M. / Yonemochi, M. / Hanada, K. / Shirouzu, M. / Zhang, K.Y.J.
CitationJournal: Int.J.Biol.Macromol. / Year: 2022
Title: Crystal structure of human acetylcholinesterase in complex with tacrine: Implications for drug discovery
Authors: Dileep, K. / Ihara, K. / Mishima-Tsumagari, C. / Kukimoto-Niino, M. / Yonemochi, M. / Hanada, K. / Shirouzu, M. / Zhang, K.Y.
History
DepositionFeb 8, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 16, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 1, 2023Group: 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.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)120,3666
Polymers118,4662
Non-polymers1,9004
Water1,02757
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5430 Å2
ΔGint11 kcal/mol
Surface area36800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.105, 105.105, 322.150
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein Acetylcholinesterase / AChE


Mass: 59232.863 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACHE / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P22303, acetylcholinesterase
#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: Chemical ChemComp-E20 / 1-BENZYL-4-[(5,6-DIMETHOXY-1-INDANON-2-YL)METHYL]PIPERIDINE / E2020


Mass: 379.492 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H29NO3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 57 / Source method: isolated from a natural source / Formula: H2O
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: 4.34 Å3/Da / Density % sol: 71.63 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 9
Details: 100 mM Tris HCl buffer pH 9.0, 20 % PEG 3350, 200 mM KNO3
PH range: 8.0 - 9.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL26B2 / Wavelength: 1 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Jul 18, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.45→47.2 Å / Num. obs: 77020 / % possible obs: 100 % / Redundancy: 22.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.122 / Net I/σ(I): 23.9 / Num. measured all: 1708002
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Net I/σ(I) obs% possible all
2.45-2.522.60.95410221345210.9494.1100
12.25-47.217.80.034130497350.99965.598.5

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.5.21data scaling
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.25data extraction
PHASER1.17.1-3600phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EY7

4ey7


Resolution: 2.45→47.2 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 24.01 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2242 3872 5.03 %
Rwork0.1937 73036 -
obs0.1953 76908 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 116.2 Å2 / Biso mean: 41.2213 Å2 / Biso min: 21.64 Å2
Refinement stepCycle: final / Resolution: 2.45→47.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8181 0 132 57 8370
Biso mean--64.76 38.71 -
Num. residues----1054
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 28 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.45-2.480.28481220.249825662688
2.48-2.510.29381270.23725952722
2.51-2.540.29631130.23825672680
2.54-2.580.25611340.224725782712
2.58-2.620.27551570.230125522709
2.62-2.660.26771340.219825602694
2.66-2.70.29451470.224726012748
2.7-2.740.29541390.224225272666
2.74-2.790.24981010.224526202721
2.79-2.840.32781510.227726202771
2.84-2.890.28411240.219925832707
2.89-2.950.26661420.225525322674
2.95-3.020.25861430.223726112754
3.02-3.090.28311200.232626232743
3.09-3.160.28771360.22625712707
3.16-3.250.24031370.227126012738
3.25-3.340.2431220.221825812703
3.35-3.450.2688920.211326452737
3.45-3.580.23071370.207726252762
3.58-3.720.25661040.196826412745
3.72-3.890.2111660.182926142780
3.89-4.090.19051570.168325662723
4.09-4.350.18521660.160826242790
4.35-4.690.16621550.144826042759
4.69-5.160.1911770.154926072784
5.16-5.90.20131600.177226692829
5.9-7.430.2211420.176627062848
7.43-47.20.17781670.171928473014

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