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- PDB-7p1n: Crystal structure of human acetylcholinesterase in complex with (... -

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Basic information

Entry
Database: PDB / ID: 7p1n
TitleCrystal structure of human acetylcholinesterase in complex with (2R,3R,4S,5S,6R)-2-{4-[1-(4-{5-hydroxy-6-[(E)-(hydroxyimino)methyl]pyridin-2-yl}butyl)-1H-1,2,3-triazol-4-yl]butoxy}-6-(hydroxymethyl)oxane-3,4,5-triol oxime
Components(Acetylcholinesterase) x 2
KeywordsHYDROLASE / cholinesterase / glucoconjugated oximes
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 / cell adhesion / hydrolase activity / 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-4J1 / Acetylcholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsDa Silva, O. / Dias, J. / Nachon, F.
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 1.0Jun 8, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 16, 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)123,86154
Polymers118,5084
Non-polymers5,35350
Water3,801211
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area28020 Å2
ΔGint-486 kcal/mol
Surface area39400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)212.290, 212.290, 116.085
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: isolated from a genetically manipulated source
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 , 6 types, 258 molecules

#6: Chemical ChemComp-4J1 / (2R,3R,4S,5S,6R)-2-[4-[1-[4-[6-[(Z)-hydroxyiminomethyl]-5-oxidanyl-pyridin-2-yl]butyl]-1,2,3-triazol-4-yl]butoxy]-6-(hydroxymethyl)oxane-3,4,5-triol


Mass: 495.526 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H33N5O8 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: SO4
#8: Chemical...
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 26 / Source method: obtained synthetically / Formula: Cl
#9: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#10: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Mg
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / 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: 6.25 Å3/Da / Density % sol: 80.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / 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: 0.8731 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 3, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8731 Å / Relative weight: 1
ReflectionResolution: 2.95→78.33 Å / Num. obs: 62748 / % possible obs: 99.92 % / Redundancy: 7.6 % / Biso Wilson estimate: 71.47 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.09202 / Net I/σ(I): 16.27
Reflection shellResolution: 2.95→3.055 Å / Rmerge(I) obs: 0.6054 / Mean I/σ(I) obs: 2.85 / Num. measured obs: 48332 / Num. unique obs: 6237 / CC1/2: 0.915

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
MOSFLM1.19.2_4158data reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EY4

4ey4


Resolution: 2.95→78.33 Å / SU ML: 0.3314 / Cross valid method: FREE R-VALUE / Phase error: 24.4595
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2047 --
Rwork0.1719 59904 -
all-478936 -
obs-62748 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 83.96 Å2
Refinement stepCycle: LAST / Resolution: 2.95→78.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8315 0 305 211 8831
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00888833
X-RAY DIFFRACTIONf_angle_d1.093312080
X-RAY DIFFRACTIONf_chiral_restr0.05761310
X-RAY DIFFRACTIONf_plane_restr0.01071566
X-RAY DIFFRACTIONf_dihedral_angle_d16.63753168
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.95-2.990.34731560.31722721X-RAY DIFFRACTION99.97
2.99-3.040.33911650.28252630X-RAY DIFFRACTION99.96
3.04-3.090.30441330.27452713X-RAY DIFFRACTION99.93
3.09-3.150.31391090.27432780X-RAY DIFFRACTION99.9
3.15-3.210.33551510.26382696X-RAY DIFFRACTION99.96
3.21-3.280.24871360.24942708X-RAY DIFFRACTION99.96
3.28-3.350.28631440.21492686X-RAY DIFFRACTION99.93
3.35-3.430.23271190.21492757X-RAY DIFFRACTION99.93
3.43-3.510.23721540.19622694X-RAY DIFFRACTION100
3.51-3.610.22071300.1892722X-RAY DIFFRACTION100
3.61-3.710.19851360.1772710X-RAY DIFFRACTION99.93
3.71-3.830.2121360.16442710X-RAY DIFFRACTION99.96
3.83-3.970.19121360.17252721X-RAY DIFFRACTION100
3.97-4.130.1891430.15442719X-RAY DIFFRACTION99.97
4.13-4.320.18681000.13252781X-RAY DIFFRACTION100
4.32-4.540.15841280.13022719X-RAY DIFFRACTION100
4.54-4.830.15591750.1232714X-RAY DIFFRACTION100
4.83-5.20.14351340.13562714X-RAY DIFFRACTION100
5.2-5.720.17471470.15772729X-RAY DIFFRACTION99.93
5.72-6.550.21661430.16412743X-RAY DIFFRACTION99.9
6.55-8.250.18991580.15862737X-RAY DIFFRACTION100
8.26-78.330.18441390.1582800X-RAY DIFFRACTION99.26
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)
13.5006932075-0.6439575564150.9515906806851.85806305113-0.1764424749311.447364336490.02340863328990.281620852642-0.481526381289-0.0963191808112-0.0170209441177-0.0151701414463-0.0580159458269-0.01406891179320.003683257081020.531891902428-0.005626189220550.07834634500730.458728963525-0.09715528382950.422258902106-126.03589946427.5982779798-45.2313963905
23.1334379471-0.2738875725740.6563771227492.52295083193-0.4821613132021.957141833560.221945637611-0.0441946458056-0.858829481213-0.0215988843029-0.0771498177204-0.08417119454330.1616576369440.202572537147-0.1239529884680.5143534801250.01313166327830.03392894063640.4400831005250.06810187851740.718613702804-77.521075595513.9000160795-11.2344988633
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain aa
2X-RAY DIFFRACTION1chain A
3X-RAY DIFFRACTION2chain bb
4X-RAY DIFFRACTION2chain B

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