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- PDB-1h23: Structure of acetylcholinesterase (E.C. 3.1.1.7) complexed with (... -

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Entry
Database: PDB / ID: 1h23
TitleStructure of acetylcholinesterase (E.C. 3.1.1.7) complexed with (S,S)-(-)-bis(12)-hupyridone at 2.15A resolution
ComponentsACETYLCHOLINESTERASE
KeywordsHYDROLASE / SERINE HYDROLASE / ACETYLCHOLINESTERASE / NEUROTRANSMITTER CLEAVAGE / ALZHEIMER'S DISEASE / BIVALENT LIGAND / DUAL-SITE BINDING / INHIBITOR / HUPERZINE A / SERINE ESTERASE SYNAPSE / MEMBRANE / NERVE / MUSCLE / GPI-ANCHOR NEUROTRANSMITTER DEGRADATION / GLYCOPROTEIN / BIS(12)-HUPYRID
Function / homology
Function and homology information


acetylcholine catabolic process in synaptic cleft / choline metabolic process / acetylcholinesterase / acetylcholinesterase activity / synaptic cleft / side of membrane / synapse / extracellular space / plasma membrane
Similarity search - Function
Acetylcholinesterase, fish/snake / : / 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, catalytic domain ...Acetylcholinesterase, fish/snake / : / 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, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-E12 / Acetylcholinesterase
Similarity search - Component
Biological speciesTORPEDO CALIFORNICA (Pacific electric ray)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsWong, D.M. / Greenblatt, H.M. / Carlier, P.R. / Han, Y.F. / Pang, Y.P. / Silman, I. / Sussman, J.L.
Citation
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.
#1: Journal: Angew.Chem.Int.Ed.Engl. / Year: 2000
Title: Dimerization of an Inactive Fragment of Huperzine a Produces a Drug with Twice the Potency of the Natural Product
Authors: Carlier, P.R. / Du, D.-M. / Han, Y.-F. / Liu, J. / Perola, E. / Williams, I.D. / Pang, Y.-P.
#2: Journal: Nat.Struct.Biol. / Year: 1997
Title: Structure of Acetylcholinesterase Complexed with the Nootropic Alkaloid, (-)-Huperzine A
Authors: Raves, M.L. / Harel, M. / Pang, Y.-P. / Silman, I. / Kozikowski, A.P. / Sussman, J.L.
#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: 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
DepositionJul 30, 2002Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 23, 2002Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2011Group: Advisory / Atomic model ...Advisory / Atomic model / Derived calculations / Non-polymer description / Other / Refinement description / Version format compliance
Revision 1.2Jan 22, 2014Group: Database references
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: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Structure summary
Category: chem_comp / database_PDB_caveat ...chem_comp / database_PDB_caveat / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _database_PDB_caveat.text / _entity.pdbx_description / _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
Revision 1.7Nov 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

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Assembly

Deposited unit
A: ACETYLCHOLINESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,2624
Polymers61,3251
Non-polymers9373
Water4,846269
1
A: ACETYLCHOLINESTERASE
hetero molecules

A: ACETYLCHOLINESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,5248
Polymers122,6502
Non-polymers1,8746
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_556y,x,-z+11
Unit cell
Length a, b, c (Å)111.794, 111.794, 137.775
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 BIVALENT HUPA-LIKE DIMER, (S, S)-(-)-BIS(12)-HUPYRIDONE ((S, S)-(-)-N, N'-DI-5'- -[5', 6', 7', 8'-TETRAHYDRO-2'(1'H)-QUINOLINONYL] 1, 12-DIAMINODODECANE) DIHYDROCHLORIDE, WITH ONE ...Details: SYNTHETIC BIVALENT HUPA-LIKE DIMER, (S, S)-(-)-BIS(12)-HUPYRIDONE ((S, S)-(-)-N, N'-DI-5'- -[5', 6', 7', 8'-TETRAHYDRO-2'(1'H)-QUINOLINONYL] 1, 12-DIAMINODODECANE) DIHYDROCHLORIDE, WITH ONE MONOMER UNIT BOUND TO THE 'ANIONIC' SUBSITE, NEAR THE BOTTOM OF THE ACTIVE SITE GORGE, AND THE SECOND MONOMER UNIT BOUND TO THE 'PERIPHERAL' ANIONIC SITE AT THE TOP OF THE GORGE, THUS 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: Chemical ChemComp-E12 / (S,S)-(-)-N,N'-DI-5'-[5',6',7',8'-TETRAHYDRO- 2'(1'H)-QUINOLYNYL]-1,12-DIAMINODODECANE DIHYDROCHLORIDE


Mass: 494.712 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H46N4O2
#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


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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 269 / 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. (-)-HUPERZINE A ((-)-HUPA), A NATURAL PRODUCT USED IN TRADITIONAL CHINESE HERBAL MEDICINE, IS AMONG THE POTENT ACHE INHIBITORS USED IN THIS TREATMENT. THE LIGAND, (S,S)-(-)-BIS(12)-HUPYRIDONE ((S,S)-(-)-N,N'-DI-5'-[5',6',7',8'-TETRAHYDRO-2'(1'H)- QUINOLINONYL]-1,12-DIAMINODODECANE) DIHYDROCHLORIDE, AN ALKYLENE LINKED DIMER OF FRAGMENTS OF THE HUPA STRUCTURE, HUPYRIDONE (5-AMINO-5,6,7,8-TETRAHYDROQUINOLINONE), HAVE BEEN SHOWN TO EXHIBIT POTENT INHIBITION OF ACHE. ONE HUPYRIDONE UNIT BINDS TO THE 'ANIONIC' SUBSITE OF THE ACTIVE SITE, NEAR THE BOTTOM OF THE ACTIVE SITE GORGE OF TCACHE, ADJACENT TO TRP84, AS SEEN FOR THE TCACHE/(-)-HUPA COMPLEX, AND THE SECOND HUPYRIDONE UNIT NEAR TO TRP279 IN THE 'PERIPHERAL' ANIONIC SITE AT THE TOP OF THE GORGE, THUS SPANNING THE ACTIVE SITE GORGE.
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: 4.11 Å3/Da / Density % sol: 69.65 %
Crystal growTemperature: 277 K / pH: 5.8
Details: PROTEIN WAS CRYSTALLISED FROM 28-30% V/V PEG 200 0.5M MES PH 5.8 AT 4 DEG. CELSIUS; THEN SOAKED IN IN MOTHER LIQUOR (40% V/V PEG 200 IN 0.1 M MES BUFFER, PH 5.8) CONTAINING 10MM (S,S)-(-)- ...Details: PROTEIN WAS CRYSTALLISED FROM 28-30% V/V PEG 200 0.5M MES PH 5.8 AT 4 DEG. CELSIUS; THEN SOAKED IN IN MOTHER LIQUOR (40% V/V PEG 200 IN 0.1 M MES BUFFER, PH 5.8) CONTAINING 10MM (S,S)-(-)-BIS(12)-HUPYRIDONE DIHYDROCHLORIDE FOR 2 DAYS
Crystal grow
*PLUS
Temperature: 4 ℃ / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
140 %(v/v)PEG2001drop
20.5 MMES1droppH5.8
328-30 %(v/v)PEG2001reservoir
40.5 MMES1reservoirpH5.8

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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: Sep 5, 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: 2.15→29.3 Å / Num. obs: 54602 / % possible obs: 99.7 % / Redundancy: 0.38 % / Rmerge(I) obs: 0.066 / Net I/σ(I): 13.5
Reflection shellResolution: 2.15→2.23 Å / Redundancy: 9.79 % / Rmerge(I) obs: 0.396 / % possible all: 99.8
Reflection
*PLUS
Num. all: 54602 / Num. obs: 54392 / Num. measured all: 536295
Reflection shell
*PLUS
% possible obs: 99.8 %

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Processing

Software
NameVersionClassification
CNS1refinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2ACE

2ace


Resolution: 2.15→29.3 Å / Rfactor Rfree error: 0.00415 / Data cutoff high absF: 10000 / 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 THR 535. 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 THR 535. SEVERAL RESIDUES MISSING IN CHAIN BREAK, FROM HIS 486 - GLU 489 (INCLUSIVE).
RfactorNum. reflection% reflectionSelection details
Rfree0.2148 2677 4.9 %RANDOM
Rwork0.1893 ---
obs0.1893 53657 98.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 34.7 Å2 / ksol: 0.345 e/Å3
Displacement parametersBiso mean: 34.753 Å2
Baniso -1Baniso -2Baniso -3
1--7.197 Å2-0.949 Å20 Å2
2---7.197 Å20 Å2
3---14.394 Å2
Refinement stepCycle: LAST / Resolution: 2.15→29.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4184 0 64 269 4517
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.019531
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_deg1.94229
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.2321.5
X-RAY DIFFRACTIONc_mcangle_it1.8542
X-RAY DIFFRACTIONc_scbond_it2.1072
X-RAY DIFFRACTIONc_scangle_it3.0522.5
LS refinement shellResolution: 2.15→2.25 Å / Rfactor Rfree error: 0.0174 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.313 322 4.9 %
Rwork0.2691 6304 -
obs--98.26 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2E12.PARE12-1.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4CARBOHYDRATE.PARAMCARBOHYDRATE.TOP
Refinement
*PLUS
Num. reflection obs: 54357 / % reflection Rfree: 5 % / Rfactor Rfree: 0.215 / Rfactor Rwork: 0.189
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.02
X-RAY DIFFRACTIONc_angle_deg1.94

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