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- PDB-7p1p: Crystal structure of human acetylcholinesterase in complex with (... -

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Basic information

Entry
Database: PDB / ID: 7p1p
TitleCrystal structure of human acetylcholinesterase in complex with (E)-3-hydroxy-6-(3-(4-(4-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butyl)-1H-1,2,3-triazol-1-yl)propyl)picolinaldehyde oxime
Components(Acetylcholinesterase) x 2
KeywordsHYDROLASE / Acetylcholinesterase / / antidote / oxime
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-4IX / Acetylcholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.03 Å
AuthorsOphelie, D.S. / Jose, D. / Florian, N.
Funding support France, 1items
OrganizationGrant numberCountry
Agence Nationale de la Recherche (ANR) France
CitationJournal: J.Med.Chem. / Year: 2022
Title: A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning.
Authors: Da Silva, O. / Probst, N. / Landry, C. / Hanak, A.S. / Warnault, P. / Coisne, C. / Calas, A.G. / Gosselet, F. / Courageux, C. / Gastellier, A.J. / Trancart, M. / Baati, R. / Dehouck, M.P. / ...Authors: Da Silva, O. / Probst, N. / Landry, C. / Hanak, A.S. / Warnault, P. / Coisne, C. / Calas, A.G. / Gosselet, F. / Courageux, C. / Gastellier, A.J. / Trancart, M. / Baati, R. / Dehouck, M.P. / Jean, L. / Nachon, F. / Renard, P.Y. / Dias, J.
History
DepositionJul 2, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 29, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 23, 2022Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.year
Revision 1.2Mar 16, 2022Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Apr 6, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Jun 8, 2022Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.5Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.6Nov 13, 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
aa: Acetylcholinesterase
A: Acetylcholinesterase
bb: Acetylcholinesterase
B: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,28649
Polymers118,5084
Non-polymers4,77745
Water3,621201
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area27710 Å2
ΔGint-450 kcal/mol
Surface area39530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)211.863, 211.863, 116.269
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 , 2 types, 4 molecules aabbAB

#1: Protein Acetylcholinesterase / AChE


Mass: 27775.518 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
#2: Protein Acetylcholinesterase / AChE


Mass: 31478.549 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, 3 molecules

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


Type: oligosaccharide / Mass: 732.682 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1221m-1a_1-5]/1-1-2-3/a4-b1_a6-d1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#4: 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.: 1 / Source method: obtained synthetically
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
#5: Polysaccharide N-acetyl-alpha-neuraminic acid-(2-3)-beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 674.604 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
DNeup5Aca2-3DGalpb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,3,2/[a2122h-1b_1-5_2*NCC/3=O][a2112h-1b_1-5][Aad21122h-2a_2-6_5*NCC/3=O]/1-2-3/a4-b1_b3-c2WURCSPDB2Glycan 1.1.0
[][b-D-GlcpNAc]{[(4+1)][b-D-Galp]{[(3+2)][a-D-Neup5Ac]{}}}LINUCSPDB-CARE

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Non-polymers , 5 types, 243 molecules

#6: Chemical ChemComp-4IX / (2R,3R,4S,5S,6R)-2-[4-[1-[3-[6-[(Z)-hydroxyiminomethyl]-5-oxidanyl-pyridin-2-yl]propyl]-1,2,3-triazol-4-yl]butoxy]-6-(hydroxymethyl)oxane-3,4,5-triol


Mass: 481.500 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H31N5O8 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: SO4
#8: Chemical...
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 22 / Source method: obtained synthetically / Formula: Cl
#9: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: Mg
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 201 / 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: 6.38 Å3/Da / Density % sol: 80.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 1.5 M LiSO4, 100 mM HEPES, 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: 0.8731 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 4, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8731 Å / Relative weight: 1
ReflectionResolution: 3.03→91.74 Å / Num. obs: 57768 / % possible obs: 99.86 % / Redundancy: 7.4 % / Biso Wilson estimate: 78.77 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.108 / Rrim(I) all: 0.1161 / Net I/σ(I): 13.06
Reflection shellResolution: 3.03→3.138 Å / Num. unique obs: 5756 / CC1/2: 0.933

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
MOSFLM1.17.1_3660data reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EY4

4ey4


Resolution: 3.03→91.74 Å / SU ML: 0.4425 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 27.0998
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2216 2843 4.9 %
Rwork0.1903 55146 -
obs0.1923 57768 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 88 Å2
Refinement stepCycle: LAST / Resolution: 3.03→91.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8315 0 268 201 8784
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00988798
X-RAY DIFFRACTIONf_angle_d1.213312037
X-RAY DIFFRACTIONf_chiral_restr0.0631305
X-RAY DIFFRACTIONf_plane_restr0.01271563
X-RAY DIFFRACTIONf_dihedral_angle_d9.60061259
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.03-3.080.46421550.42462730X-RAY DIFFRACTION99.9
3.08-3.130.4461390.39132747X-RAY DIFFRACTION99.9
3.13-3.190.39291420.32832730X-RAY DIFFRACTION99.9
3.19-3.260.32551850.28432706X-RAY DIFFRACTION99.9
3.26-3.330.27941460.25252733X-RAY DIFFRACTION99.93
3.33-3.410.26721210.22732798X-RAY DIFFRACTION99.97
3.41-3.490.241110.22192757X-RAY DIFFRACTION99.97
3.49-3.590.25661730.22752708X-RAY DIFFRACTION99.93
3.59-3.690.30031340.21752740X-RAY DIFFRACTION99.79
3.69-3.810.25111540.21662744X-RAY DIFFRACTION99.97
3.81-3.950.2561140.2242783X-RAY DIFFRACTION99.97
3.95-4.110.20011430.16532750X-RAY DIFFRACTION99.97
4.11-4.290.18271460.14942772X-RAY DIFFRACTION100
4.29-4.520.17581460.14632751X-RAY DIFFRACTION100
4.52-4.80.18761490.1372747X-RAY DIFFRACTION99.93
4.8-5.170.17641390.14832787X-RAY DIFFRACTION99.93
5.17-5.690.18881260.16592754X-RAY DIFFRACTION99.72
5.69-6.520.18591550.17752779X-RAY DIFFRACTION99.76
6.52-8.210.17091470.16792775X-RAY DIFFRACTION99.76
8.21-91.740.18991180.1672855X-RAY DIFFRACTION99.1
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)
13.02097821815-0.9478365360.557731008762.40567033143-0.5149507841571.51306524239-0.0917572187923-0.219706366784-0.1547706918550.1593958603840.08214869747070.2951928305030.02021629757740.03517025305530.01495441241560.470854192915-0.03947337604980.09492052374630.508661432271-0.02955267981180.4405862895286.9033232326-94.95975796847.31481855034
22.51982040849-0.3212750348710.7673116022782.5214042623-0.3563102547051.89154836898-0.0244668011891-0.188158490892-0.247513461403-0.1056087412740.182977982340.724501590463-0.106587446468-0.302437102737-0.1399444312560.453528707329-0.0223736972158-0.02880296223660.568235877248-0.02429028281280.79731463661450.6084489762-60.1670181481-26.6309056013
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsLabel asym-IDLabel seq-ID
1X-RAY DIFFRACTION1chain aaA - F1
2X-RAY DIFFRACTION1chain A
3X-RAY DIFFRACTION2chain bbG - M1
4X-RAY DIFFRACTION2chain B

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