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- PDB-6f25: Crystal structure of human acetylcholinesterase in complex with C35. -

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Basic information

Entry
Database: PDB / ID: 6f25
TitleCrystal structure of human acetylcholinesterase in complex with C35.
ComponentsAcetylcholinesterase
KeywordsHYDROLASE / Acetylcholinesterase
Function / homology
Function and homology information


negative regulation of synaptic transmission, cholinergic / serine hydrolase activity / Neurotransmitter clearance / acetylcholine catabolic process in synaptic cleft / cholinesterase activity / acetylcholine catabolic process / acetylcholinesterase / amyloid precursor protein metabolic process / acetylcholine binding / acetylcholine receptor signaling pathway ...negative regulation of synaptic transmission, cholinergic / serine hydrolase activity / Neurotransmitter clearance / acetylcholine catabolic process in synaptic cleft / cholinesterase activity / acetylcholine catabolic process / acetylcholinesterase / amyloid precursor protein metabolic process / acetylcholine binding / acetylcholine receptor signaling pathway / osteoblast development / acetylcholinesterase activity / Synthesis of PC / basement membrane / regulation of receptor recycling / Synthesis, secretion, and deacylation of Ghrelin / synaptic cleft / synapse assembly / side of membrane / laminin binding / collagen binding / positive regulation of protein secretion / neuromuscular junction / receptor internalization / nervous system development / amyloid-beta binding / positive regulation of cold-induced thermogenesis / 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, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase type B, active site / Carboxylesterases type-B serine active site. / Carboxylesterase, type B / Carboxylesterase family ...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, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-CVZ / Acetylcholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.05199647812 Å
AuthorsDias, J. / Nachon, F.
Funding support France, 1items
OrganizationGrant numberCountry
Ministry of armed forcesPDH-2-NRBC-4-C-4202 France
CitationJournal: Neuropharmacology / Year: 2019
Title: New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer's disease.
Authors: Zueva, I. / Dias, J. / Lushchekina, S. / Semenov, V. / Mukhamedyarov, M. / Pashirova, T. / Babaev, V. / Nachon, F. / Petrova, N. / Nurullin, L. / Zakharova, L. / Ilyin, V. / Masson, P. / Petrov, K.
History
DepositionNov 23, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 12, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_PDB_caveat / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_validate_chiral / pdbx_validate_close_contact / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _database_PDB_caveat.text / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_chiral.auth_asym_id / _pdbx_validate_chiral.auth_seq_id / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag
Revision 2.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)123,41749
Polymers118,2072
Non-polymers5,20947
Water3,693205
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9030 Å2
ΔGint-300 kcal/mol
Surface area39340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)211.074, 211.074, 115.725
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: 59103.738 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-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][b-L-Fucp]{}}}LINUCSPDB-CARE
#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-3)-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
DGlcpNAcb1-3DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a3-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(3+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: 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.: 1
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

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Non-polymers , 4 types, 248 molecules

#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-CVZ / 3-[(~{E})-5-[ethyl-[(2-nitrophenyl)methyl]amino]pent-1-enyl]-1-[5-[ethyl-[(2-nitrophenyl)methyl]amino]pentyl]-6-methyl-pyrimidine-2,4-dione


Mass: 620.739 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H44N6O6
#7: Chemical...
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 29 / Source method: obtained synthetically / Formula: Cl
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 205 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 6.33 Å3/Da / Density % sol: 80.58 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 1.5 M LiSo4, 100 mM Hepes pH 7, 60 mM MgSo4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.87313 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Jul 21, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.87313 Å / Relative weight: 1
ReflectionResolution: 3.05→48.89 Å / Num. obs: 55240 / % possible obs: 98.9 % / Redundancy: 11.9 % / Biso Wilson estimate: 78.548294483 Å2 / Rmerge(I) obs: 0.05284 / Rrim(I) all: 0.07473 / Net I/σ(I): 11.6
Reflection shellResolution: 3.05→3.16 Å / Rmerge(I) obs: 0.6606 / Rrim(I) all: 0.9343

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LII

3lii


Resolution: 3.05199647812→48.8888375148 Å / SU ML: 0.413789398865 / Cross valid method: FREE R-VALUE / σ(F): 1.33784247226 / Phase error: 23.6314281526
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.214156664726 2746 4.97833535778 %
Rwork0.178073125798 52413 -
obs0.179826801437 55159 98.702669816 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 80.7123371356 Å2
Refinement stepCycle: LAST / Resolution: 3.05199647812→48.8888375148 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8304 0 297 205 8806
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002796215811858858
X-RAY DIFFRACTIONf_angle_d0.73381040005412139
X-RAY DIFFRACTIONf_chiral_restr0.04363474678781296
X-RAY DIFFRACTIONf_plane_restr0.005262228789841579
X-RAY DIFFRACTIONf_dihedral_angle_d9.516857687447009
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.052-3.10460.3993790691311170.3710583166212250X-RAY DIFFRACTION85.0215517241
3.1046-3.16110.4423192933641250.3486786670062434X-RAY DIFFRACTION92.6838102137
3.1611-3.22180.3294491748411460.3066038399582564X-RAY DIFFRACTION97.272074659
3.2218-3.28760.3400816838191420.2763847076912625X-RAY DIFFRACTION99.7836278399
3.2876-3.35910.3086339197931470.2518124273052624X-RAY DIFFRACTION99.89185292
3.3591-3.43720.2633879839431370.2428948478992652X-RAY DIFFRACTION99.9283410964
3.4372-3.52310.2943851272271560.232250776352612X-RAY DIFFRACTION99.9638858794
3.5231-3.61830.2343322011511150.2058526860162667X-RAY DIFFRACTION99.9281609195
3.6183-3.72480.2415193730821670.1816078920392631X-RAY DIFFRACTION99.9642729546
3.7248-3.8450.2369115049561350.1688078145572634X-RAY DIFFRACTION99.963898917
3.845-3.98230.2048597632271420.1604394941762671X-RAY DIFFRACTION100
3.9823-4.14170.1781175441761290.1475568323532660X-RAY DIFFRACTION100
4.1417-4.33010.1874939951561320.1416980604082631X-RAY DIFFRACTION100
4.3301-4.55820.1695407437311350.1311599846122677X-RAY DIFFRACTION100
4.5582-4.84360.1542810712471250.1284393478762665X-RAY DIFFRACTION100
4.8436-5.21710.1609102768861580.1359195866522646X-RAY DIFFRACTION100
5.2171-5.74140.1665908765681520.1541868129272635X-RAY DIFFRACTION100
5.7414-6.57050.1969761464911250.1668353404392686X-RAY DIFFRACTION100
6.5705-8.27170.2088067146971430.1656916577082705X-RAY DIFFRACTION100
8.2717-48.89510.1919418197171180.179996126182744X-RAY DIFFRACTION99.5132127955

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