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- PDB-1odc: STRUCTURE OF ACETYLCHOLINESTERASE (E.C. 3.1.1.7) COMPLEXED WITH N... -

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Entry
Database: PDB / ID: 1odc
TitleSTRUCTURE OF ACETYLCHOLINESTERASE (E.C. 3.1.1.7) COMPLEXED WITH N-4'-QUINOLYL-N'-9"-(1",2",3",4"-TETRAHYDROACRIDINYL)-1,8- DIAMINOOCTANE AT 2.2A RESOLUTION
ComponentsACETYLCHOLINESTERASE
KeywordsHYDROLASE / SERINE HYDROLASE / NEUROTRANSMITTER CLEAVAGE / ALZHEIMER'S DISEASE / BIVALENT LIGAND / DUAL-SITE BINDING / INHIBITOR / SERINE ESTERASE SYNAPSE / NERVE / MUSCLE / GPI-ANCHOR NEUROTRANSMITTER DEGRADATION / GLYCOPROTEIN
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-A8B / Acetylcholinesterase
Similarity search - Component
Biological speciesTORPEDO CALIFORNICA (Pacific electric ray)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsWong, D.M. / Greenblatt, H.M. / Carlier, P.R. / Han, Y.-F. / Pang, Y.-P. / Silman, I. / Sussman, J.L.
Citation
Journal: J.Med.Chem. / Year: 2006
Title: Complexes of Alkylene-Linked Tacrine Dimers with Torpedo Californica Acetylcholinesterase: Binding of Bis(5)-Tacrine Produces a Dramatic Rearrangement in the Active-Site Gorge.
Authors: Rydberg, E.H. / Brumshtein, B. / Greenblatt, H.M. / Wong, D.M. / Shaya, D. / Williams, L.D. / Carlier, P.R. / Pang, Y.-P. / Silman, I. / Sussman, J.L.
#1: Journal: J.Am.Chem.Soc. / Year: 2003
Title: Acetylcholinesterase Complexed with Bivalent Ligands Related to Huperzine A: Experimental Evidence for Species-Dependent Protein-Ligand Complementarity
Authors: Wong, D.M. / Greenblatt, H.M. / Dvir, H. / Carlier, P.R. / Han, Y.-F. / Pang, Y.-P. / Silman, I. / Sussman, J.L.
#2: Journal: J.Med.Chem. / Year: 1999
Title: Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors: Investigating Ligand-Peripheral Site Interactions
Authors: Carlier, P.R. / Chow, E.S.-H. / Han, Y.-F. / Liu, J. / El Yazal, J. / Pang, Y.-P.
#3: Journal: J. Comput. Aided Mol. Des. / Year: 1994
Title: Prediction of the Binding Sites of Huperzine a in Acetylcholinesterase by Docking Studies
Authors: Pang, Y.-P. / Kozikowski, A.P.
#4: Journal: Proc.Natl.Acad.Sci.USA / Year: 1993
Title: Quaternary Ligand Binding to Aromatic Residues in the Active-Site Gorge of Acetylcholinesterase
Authors: Harel, M. / Schalk, I. / Ehret-Sabatier, L. / Bouet, F. / Goeldner, M. / Hirth, C. / Axelsen, P.H. / Silman, I. / Sussman, J.L.
#5: Journal: Science / Year: 1991
Title: Atomic Structure of Acetylcholinesterase from Torpedo Californica: A Prototypic Acetylcholine-Binding Protein
Authors: Sussman, J.L. / Harel, M. / Frolow, F. / Oefner, C. / Goldman, A. / Toker, L. / Silman, I.
History
DepositionFeb 15, 2003Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 23, 2005Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Apr 3, 2019Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Experimental preparation / Other
Category: citation / exptl_crystal_grow ...citation / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_conn
Item: _citation.country / _exptl_crystal_grow.temp ..._citation.country / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval / _struct_conn.pdbx_leaving_atom_flag
Revision 1.4Jul 29, 2020Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_database_status / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5May 12, 2021Group: Derived calculations / Structure summary
Category: chem_comp / pdbx_struct_assembly ...chem_comp / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_oper_list
Item: _chem_comp.pdbx_synonyms / _pdbx_struct_assembly.details ..._chem_comp.pdbx_synonyms / _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details / _pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details
Revision 1.6Dec 13, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ACETYLCHOLINESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,2204
Polymers61,3251
Non-polymers8953
Water2,756153
1
A: ACETYLCHOLINESTERASE
hetero molecules

A: ACETYLCHOLINESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,4408
Polymers122,6502
Non-polymers1,7906
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_556y,x,-z+11
Unit cell
Length a, b, c (Å)111.487, 111.487, 136.744
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein ACETYLCHOLINESTERASE / / ACHE


Mass: 61325.090 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Details: SYNTHETIC HETEROBIVALENT TACRINE-BASED DIMER, A8B (N-4'-QUINOLYL-N'-9"-(1", 2", 3", 4" -TETRAHYDROACRIDINYL)-1, 8-DIAMINOOCTANE) DIHYDROCHLORIDE WITH THE TACRINE MOIETY BOUND TO THE ...Details: SYNTHETIC HETEROBIVALENT TACRINE-BASED DIMER, A8B (N-4'-QUINOLYL-N'-9"-(1", 2", 3", 4" -TETRAHYDROACRIDINYL)-1, 8-DIAMINOOCTANE) DIHYDROCHLORIDE WITH THE TACRINE MOIETY BOUND TO THE 'ANIONIC' SUBSITE, NEAR THE BOTTOM OF THE ACTIVE SITE GORGE, AND THE 4-AMINOQUINOLINE MOIETY BOUND TO THE 'PERIPHERAL' ANIONIC SITE (PAS) AT THE TOP OF THE GORGE OF TCACHE, BOTH IN A DOUBLE-STACKING SANDWICH. THE LIGAND, A8B, THUS BINDS BY SPANNING THE ACTIVE-SITE GORGE.
Source: (natural) TORPEDO CALIFORNICA (Pacific electric ray)
Organ: ELECTRIC ORGAN / Variant: G2 FORM / Tissue: ELECTROPLAQUE / References: UniProt: P04058, acetylcholinesterase
#2: 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.: 2
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
#3: Chemical ChemComp-A8B / N-QUINOLIN-4-YL-N'-(1,2,3,4-TETRAHYDROACRIDIN-9-YL)OCTANE-1,8-DIAMINE / TACRINE(8)-4-AMINOQUINOLINE


Mass: 452.634 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H36N4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 153 / Source method: isolated from a natural source / Formula: H2O
Compound detailsCOMPOUND HYDROLYZES CHOLINE RELEASED INTO THE SYNAPSE. CATALYTIC ACTIVITY: ACETYLCHOLINE + H(2)O = ...COMPOUND HYDROLYZES CHOLINE RELEASED INTO THE SYNAPSE. CATALYTIC ACTIVITY: ACETYLCHOLINE + H(2)O = CHOLINE ACETATE. INHIBITORS OF THE ENZYME ACETYLCHOLINESTERASE (ACHE) IMPROVE THE COGNITIVE ABILITIES OF INDIVIDUALS WITH EARLY STAGE ALZHEIMER'S DISEASE. 9-AMINO-1,2,3,4-TETRA- HYDROACRIDINE (TACRINE, ALSO KNOWN AS THA OR COGNEX), A SYNTHETIC COMPOUND, IS AMONG THE POTENT ACHE INHIBITORS USED IN THIS TREATMENT. THE LIGAND, A8B (N-4'-QUINOLYL-N'- 9"-(1",2",3",4" -TETRA-HYDROACRIDINYL)-1,8-DIAMINOOCTANE) DIHYDROCHLORIDE, A C8-ALKYLENE LINKED HETERODIMER OF TACRINE AND 4-AMINOQUINOLINE, WAS DESIGNED TO PROBE THE PROTEIN-LIGAND INTERACTIONS AT THE 'PERIPHEAL' ANIONIC SITE (PAS) OF THE ACTIVE-SITE GORGE OF ACHE. IT HAS BEEN SHOWN TO EXHIBIT POTENT INHIBITION OF ACHE. THE TACRINE MOIETY BINDS TO THE 'ANIONIC' SUBSITE, NEAR THE BOTTOM OF THE ACTIVE-SITE GORGE OF TCACHE, BETWEEN THE AROMATIC RINGS OF TRP84 AND PHE330, AS SEEN FOR THE TCACHE/TACRINE COMPLEX, AND THE 4-AMINOQUINOLINE MOIETY BINDS TO THE PAS AT THE TOP OF THE GORGE, BETWEEN THE AROMATIC RINGS OF TRP279 AND TYR70. THE LIGAND, A8B, THUS BINDS BY SPANNING THE ACTIVE SITE GORGE, WITH BOTH BINDING MOIETIES OF A8B BINDING IN A DOUBLE-STACKING SANDWICH.

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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: 4.06 Å3/Da / Density % sol: 69.7 %
Crystal growTemperature: 277 K / pH: 5.8
Details: PROTEIN WAS CRYSTALLISED FROM 28-33% V/V PEG 200 0.5M MES PH 5.8 AT 4 DEG. CELSIUS; THEN SOAKED IN MOTHER LIQUOR (40% V/V PEG 200 IN 0.1 M MES BUFFER, PH 5.8) CONTAINING 1MM N-4'-QUINOLYL-N'- ...Details: PROTEIN WAS CRYSTALLISED FROM 28-33% V/V PEG 200 0.5M MES PH 5.8 AT 4 DEG. CELSIUS; THEN SOAKED IN MOTHER LIQUOR (40% V/V PEG 200 IN 0.1 M MES BUFFER, PH 5.8) CONTAINING 1MM N-4'-QUINOLYL-N'-9"-(1",2", 3",4"-TETRAHYDROACRIDINYL)-1,8-DIAMINOOCTANE DIHYRDOCHLORIDE FOR ONE DAY.

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Data collection

DiffractionMean temperature: 120 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU IMAGE PLATE / Detector: IMAGE PLATE / Date: Oct 15, 2000 / Details: OSMIC BLUE CONFOCAL MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. obs: 50284 / % possible obs: 99.7 % / Redundancy: 0.35 % / Biso Wilson estimate: 26.4 Å2 / Rmerge(I) obs: 0.049 / Net I/σ(I): 23.1
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 9.81 % / Rmerge(I) obs: 0.287 / % possible all: 99.9

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Processing

Software
NameVersionClassification
CNS1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2ACE

2ace


Resolution: 2.2→29.12 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 2034289.24 / Cross valid method: THROUGHOUT / σ(F): 0
Details: SEVERAL RESIDUES ARE NOT SEEN IN THE CRYSTAL STRUCTURE, DUE TO DISORDER. THESE INCLUDE ASP 1, ASP 2, HIS 3 AND THE C-TERMINAL RESIDUES AFTER ALA 536. SEVERAL RESIDUES MISSING IN CHAIN BREAK, ...Details: SEVERAL RESIDUES ARE NOT SEEN IN THE CRYSTAL STRUCTURE, DUE TO DISORDER. THESE INCLUDE ASP 1, ASP 2, HIS 3 AND THE C-TERMINAL RESIDUES AFTER ALA 536. SEVERAL RESIDUES MISSING IN CHAIN BREAK, FROM HIS 486 - GLU 489 (INCLUSIVE). TWO WATER MOLECULES WERE FITTED WITH 0.75 OCCUPANCIES EACH (HOH Z 152 AND HOH Z 153).
RfactorNum. reflection% reflectionSelection details
Rfree0.2401 2428 4.9 %RANDOM
Rwork0.1991 ---
obs0.1991 49443 98.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 51.6 Å2 / ksol: 0.38 e/Å3
Displacement parametersBiso mean: 35.2 Å2
Baniso -1Baniso -2Baniso -3
1-7.03 Å23.07 Å20 Å2
2--7.03 Å20 Å2
3----14.04 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.24 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.14 Å0.16 Å
Refinement stepCycle: LAST / Resolution: 2.2→29.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4178 0 62 153 4393
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.02
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.9
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d24
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d1.27
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.2331.5
X-RAY DIFFRACTIONc_mcangle_it1.8112
X-RAY DIFFRACTIONc_scbond_it2.1532
X-RAY DIFFRACTIONc_scangle_it2.9942.5
LS refinement shellResolution: 2.2→2.28 Å / Rfactor Rfree error: 0.015 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.226 225 4.9 %
Rwork0.234 4544 -
obs--96.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2A8B_1.PARA8B.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4CARBOHYDRATE.PARAMCARBOHYDRATE.TOP
X-RAY DIFFRACTION5CIS_PEPTIDE.PARAM

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