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- PDB-6h14: Crystal structure of TcACHE complexed to 1-(6-oxo-1,2,3,4,6,10b-h... -

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Basic information

Entry
Database: PDB / ID: 6h14
TitleCrystal structure of TcACHE complexed to 1-(6-oxo-1,2,3,4,6,10b-hexahydropyrido[2,1-a]isoindol-10-yl)-3-(4-(1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)urea
ComponentsAcetylcholinesterase
KeywordsHYDROLASE / complex / inhibitor / alzheimer / acetylcholinesterase / multi-target-directed ligands / MTDL
Function / homology
Function and homology information


acetylcholine catabolic process in synaptic cleft / acetylcholinesterase / acetylcholinesterase activity / synaptic cleft / side of membrane / synapse / plasma membrane
Similarity search - Function
Acetylcholinesterase, fish/snake / 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 ...Acetylcholinesterase, fish/snake / 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-FW8 / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Acetylcholinesterase
Similarity search - Component
Biological speciesTetronarce californica (Pacific electric ray)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 Å
AuthorsCoquelle, N. / Colletier, J.P.
Funding support France, 1items
OrganizationGrant numberCountry
French National Research AgencyANR-12-BS07-008-01 France
CitationJournal: Eur.J.Med.Chem. / Year: 2019
Title: Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3.
Authors: Oukoloff, K. / Coquelle, N. / Bartolini, M. / Naldi, M. / Le Guevel, R. / Bach, S. / Josselin, B. / Ruchaud, S. / Catto, M. / Pisani, L. / Denora, N. / Iacobazzi, R.M. / Silman, I. / ...Authors: Oukoloff, K. / Coquelle, N. / Bartolini, M. / Naldi, M. / Le Guevel, R. / Bach, S. / Josselin, B. / Ruchaud, S. / Catto, M. / Pisani, L. / Denora, N. / Iacobazzi, R.M. / Silman, I. / Sussman, J.L. / Buron, F. / Colletier, J.P. / Jean, L. / Routier, S. / Renard, P.Y.
History
DepositionJul 10, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 15, 2019Provider: repository / Type: Initial release
Revision 2.0Oct 9, 2019Group: Atomic model / Data collection / Derived calculations
Category: atom_site / pdbx_nonpoly_scheme ...atom_site / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
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 / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_struct_assembly_prop.value
Revision 3.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / 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 / 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_alt_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.occupancy / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _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 3.1Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)131,70026
Polymers127,5282
Non-polymers4,17224
Water19,4921082
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B: Acetylcholinesterase
hetero molecules

A: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,70026
Polymers127,5282
Non-polymers4,17224
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555-x,y+1/2,-z+1/21
Buried area6520 Å2
ΔGint15 kcal/mol
Surface area39240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.591, 107.926, 150.698
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Acetylcholinesterase / / AChE


Mass: 63763.965 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Tetronarce californica (Pacific electric ray)
References: UniProt: P04058, acetylcholinesterase

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Sugars , 2 types, 6 molecules

#2: 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: obtained synthetically
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#3: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: obtained synthetically / 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 , 9 types, 1100 molecules

#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: C2H6O2
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-FW8 / 1-[(10~{b}~{S})-6-oxidanylidene-2,3,4,10~{b}-tetrahydro-1~{H}-pyrido[2,1-a]isoindol-10-yl]-3-[4-[1-[2-(1,2,3,4-tetrahydroacridin-9-ylamino)ethyl]-1,2,3-triazol-4-yl]pyridin-2-yl]urea


Mass: 613.711 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H35N9O2
#8: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL / Polyethylene glycol


Mass: 150.173 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H14O4
#9: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#10: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#11: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#12: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1082 / Source method: isolated from a natural source / Formula: H2O

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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: 2.82 Å3/Da / Density % sol: 56.42 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 50 mM Mes pH 6.0, 30% PEG 2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Jul 22, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.86→46.49 Å / Num. obs: 123623 / % possible obs: 98.36 % / Redundancy: 4.6 % / CC1/2: 0.997 / Rmerge(I) obs: 0.093 / Rrim(I) all: 0.103 / Net I/σ(I): 10.3
Reflection shellResolution: 1.86→1.93 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.964 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 11772 / CC1/2: 0.774 / Rrim(I) all: 1.08 / % possible all: 95.13

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2xi4

2xi4


Resolution: 1.86→46.49 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.59
RfactorNum. reflection% reflection
Rfree0.2111 6202 5.02 %
Rwork0.1766 --
obs0.1784 123607 98.36 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.86→46.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8432 0 279 1082 9793
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0089215
X-RAY DIFFRACTIONf_angle_d1.00612520
X-RAY DIFFRACTIONf_dihedral_angle_d13.6275521
X-RAY DIFFRACTIONf_chiral_restr0.0541294
X-RAY DIFFRACTIONf_plane_restr0.0061599
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.86-1.88110.31411840.27453677X-RAY DIFFRACTION94
1.8811-1.90330.31671950.2653722X-RAY DIFFRACTION95
1.9033-1.92650.2831730.25433821X-RAY DIFFRACTION96
1.9265-1.95090.27011770.24013902X-RAY DIFFRACTION97
1.9509-1.97650.27892080.23733816X-RAY DIFFRACTION98
1.9765-2.00360.27831960.22133927X-RAY DIFFRACTION98
2.0036-2.03220.24741960.20563894X-RAY DIFFRACTION99
2.0322-2.06260.25782100.20673863X-RAY DIFFRACTION99
2.0626-2.09480.22492240.19883860X-RAY DIFFRACTION99
2.0948-2.12910.25312180.20093900X-RAY DIFFRACTION99
2.1291-2.16590.24032040.18993883X-RAY DIFFRACTION99
2.1659-2.20520.24242240.19273906X-RAY DIFFRACTION99
2.2052-2.24770.23761980.18323905X-RAY DIFFRACTION98
2.2477-2.29350.22771980.17313799X-RAY DIFFRACTION96
2.2935-2.34340.2011990.17583921X-RAY DIFFRACTION99
2.3434-2.39790.22322310.17483889X-RAY DIFFRACTION99
2.3979-2.45790.25171990.17913953X-RAY DIFFRACTION99
2.4579-2.52430.21472040.17623933X-RAY DIFFRACTION99
2.5243-2.59860.23872110.17683920X-RAY DIFFRACTION99
2.5986-2.68250.18881990.17263980X-RAY DIFFRACTION99
2.6825-2.77830.22622260.17613936X-RAY DIFFRACTION99
2.7783-2.88960.20172110.17653954X-RAY DIFFRACTION99
2.8896-3.0210.22732020.1723931X-RAY DIFFRACTION99
3.021-3.18030.21872140.1813955X-RAY DIFFRACTION99
3.1803-3.37950.18572120.17633910X-RAY DIFFRACTION98
3.3795-3.64030.18352170.16223957X-RAY DIFFRACTION99
3.6403-4.00650.17312160.15164020X-RAY DIFFRACTION100
4.0065-4.58580.16662120.13884021X-RAY DIFFRACTION99
4.5858-5.77590.16252250.14564060X-RAY DIFFRACTION99
5.7759-46.50810.23442190.19324190X-RAY DIFFRACTION98

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