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- PDB-1h22: Structure of acetylcholinesterase (E.C. 3.1.1.7) complexed with (... -

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Basic information

Entry
Database: PDB / ID: 1h22
TitleStructure of acetylcholinesterase (E.C. 3.1.1.7) complexed with (S,S)-(-)-bis(10)-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(10)-HUPYRID
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-E10 / 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 17, 2011Group: Derived calculations / Non-polymer description ...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: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / 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 / _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

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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)62,2344
Polymers61,3251
Non-polymers9093
Water3,999222
1
A: ACETYLCHOLINESTERASE
hetero molecules

A: ACETYLCHOLINESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,4688
Polymers122,6502
Non-polymers1,8186
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_556y,x,-z+11
Unit cell
Length a, b, c (Å)111.460, 111.460, 137.337
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(10)-HUPYRIDONE ((S, S)-(-)-N, N'-DI-5'- -[5', 6', 7', 8'-TETRAHYDRO-2'(1'H)-QUINOLINONYL] -1, 10-DIAMINODECANE) DIHYDROCHLORIDE, WITH ONE ...Details: SYNTHETIC BIVALENT HUPA-LIKE DIMER, (S, S)-(-)-BIS(10)-HUPYRIDONE ((S, S)-(-)-N, N'-DI-5'- -[5', 6', 7', 8'-TETRAHYDRO-2'(1'H)-QUINOLINONYL] -1, 10-DIAMINODECANE) 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-E10 / (S,S)-(-)-N,N'-DI-5'-[5',6',7',8'-TETRAHYDRO- 2'(1'H)-QUINOLYNYL]-1,10-DIAMINODECANE DIHYDROCHLORIDE


Mass: 466.659 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H42N4O2
#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.: 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 / Water


Mass: 18.015 Da / Num. of mol.: 222 / 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(10)-HUPYRIDONE ((S,S)-(-)-N,N'-DI-5'-[5',6',7',8'-TETRAHYDRO-2'(1'H)- QUINOLINONYL]-1,10-DIAMINODECANE) 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.

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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: 69.37 %
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 MOTHER LIQUOR (40% V/V PEG 200 IN 0.1 M MES BUFFER, PH 5.8) CONTAINING 2MM (S,S)-(-)-BIS(10) ...Details: PROTEIN WAS CRYSTALLISED FROM 28-30% 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 2MM (S,S)-(-)-BIS(10)-HUPYRIDONE DIHYDROCHLORIDE FOR ONE DAY.
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: Jan 7, 2001 / 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→26.4 Å / Num. obs: 53982 / % possible obs: 95.3 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.049 / Net I/σ(I): 17.3
Reflection shellResolution: 2.15→2.23 Å / Redundancy: 10 % / Rmerge(I) obs: 0.228 / % possible all: 96.8
Reflection
*PLUS
Num. all: 53982 / Num. obs: 51434 / Num. measured all: 447124
Reflection shell
*PLUS
% possible obs: 96.8 %

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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→26.4 Å / Rfactor Rfree error: 0.004385 / 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 A1, ASP A2, HIS A3 AND THE C-TERMINAL RESIDUES AFTER THR A535. SEVERAL RESIDUES MISSING IN CHAIN ...Details: SEVERAL RESIDUES ARE NOT SEEN IN THE CRYSTAL STRUCTURE, DUE TO DISORDER. THESE INCLUDE ASP A1, ASP A2, HIS A3 AND THE C-TERMINAL RESIDUES AFTER THR A535. SEVERAL RESIDUES MISSING IN CHAIN BREAK, FROM HIS A486 - GLU A489 (INCLUSIVE). TWO ALTERNATE SIDE CHAIN CONFORMATIONS WERE FITTED FOR THE RESIDUES LEU A143 (SET TO 50% OCCUPANCY EACH), AND ARG A243 (SET TO 80% AND 20% OCCUPANCY).
RfactorNum. reflection% reflectionSelection details
Rfree0.2214 2549 4.7 %RANDOM
Rwork0.19 ---
obs0.19 51401 95 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 56.6 Å2 / ksol: 0.383 e/Å3
Displacement parametersBiso mean: 34.244 Å2
Baniso -1Baniso -2Baniso -3
1--7.141 Å2-5.601 Å20 Å2
2---7.141 Å20 Å2
3---14.283 Å2
Refinement stepCycle: LAST / Resolution: 2.15→26.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4172 0 62 222 4456
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.022286
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_deg1.94916
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_it1.2531.5
X-RAY DIFFRACTIONc_mcangle_it1.8192
X-RAY DIFFRACTIONc_scbond_it2.2092
X-RAY DIFFRACTIONc_scangle_it3.032.5
LS refinement shellResolution: 2.15→2.25 Å / Rfactor Rfree error: 0.0144 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2503 303 4.9 %
Rwork0.2232 5934 -
obs--94.98 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2E10.PARE10-1.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4CARBOHYDRATE.PARAMCARBOHYDRATE.TOP
Refinement
*PLUS
Rfactor obs: 0.19 / Rfactor Rfree: 0.221 / Rfactor Rwork: 0.19 / % reflection Rfree: 5 %
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.022
X-RAY DIFFRACTIONc_angle_deg1.95

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