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- PDB-1e66: STRUCTURE OF ACETYLCHOLINESTERASE COMPLEXED WITH (-)-HUPRINE X AT... -

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Basic information

Entry
Database: PDB / ID: 1.0E+66
TitleSTRUCTURE OF ACETYLCHOLINESTERASE COMPLEXED WITH (-)-HUPRINE X AT 2.1A RESOLUTION
ComponentsACETYLCHOLINESTERASE
KeywordsHYDROLASE / CHOLINESTERASE / HUPRINE X / ALZHEIMER'S DISEASE / CHEMICAL HYBRID
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-HUX / Acetylcholinesterase
Similarity search - Component
Biological speciesTORPEDO CALIFORNICA (Pacific electric ray)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsDvir, H. / Harel, M. / Silman, I. / Sussman, J.L.
CitationJournal: Biochemistry / Year: 2002
Title: 3D Structure of Torpedo Californica Acetylcholinesterase Complexed with Huprine X at 2. 1 A Resolution: Kinetic and Molecular Dynamic Correlates.
Authors: Dvir, H. / Wong, D.M. / Harel, M. / Barril, X. / Orozco, M. / Luque, F.J. / Munoz-Torrero, D. / Camps, P. / Rosenberry, T.L. / Silman, I. / Sussman, J.L.
History
DepositionAug 8, 2000Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 2, 2001Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2011Group: Derived calculations / Non-polymer description ...Derived calculations / Non-polymer description / Other / Refinement description / Structure summary / Version format compliance
Revision 2.0Jul 12, 2017Group: Advisory / Atomic model / Derived calculations
Category: atom_site / pdbx_unobs_or_zero_occ_atoms ...atom_site / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_site / struct_site_gen
Item: _atom_site.auth_atom_id / _atom_site.auth_comp_id ..._atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_seq_id / _atom_site.type_symbol / _struct_site.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id / _struct_site_gen.auth_seq_id
Revision 2.1Apr 3, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 2.2Jul 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 2.3Dec 13, 2023Group: 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

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Assembly

Deposited unit
A: ACETYLCHOLINESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,0664
Polymers61,3251
Non-polymers7413
Water8,953497
1
A: ACETYLCHOLINESTERASE
hetero molecules

A: ACETYLCHOLINESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,1338
Polymers122,6502
Non-polymers1,4826
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_556y,x,-z+11
Buried area3960 Å2
ΔGint-13.7 kcal/mol
Surface area38090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)112.335, 112.335, 138.165
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 HYBRID, HUPRINE X, BOUND AT THE BOTTOM OF 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-HUX / 3-CHLORO-9-ETHYL-6,7,8,9,10,11-HEXAHYDRO-7,11-METHANOCYCLOOCTA[B]QUINOLIN-12-AMINE


Mass: 298.810 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H19ClN2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 497 / Source method: isolated from a natural source / Formula: H2O
Compound detailsHYDROLYZES CHOLINE RELEASED INTO THE SYNAPSE. CATALYTIC ACTIVITY: ACETYLCHOLINE + H(2)O = CHOLINE + ...HYDROLYZES CHOLINE RELEASED INTO THE SYNAPSE. CATALYTIC ACTIVITY: ACETYLCHOLINE + H(2)O = CHOLINE + ACETATE. INHIBITORS OF THE ENZYME ACETYLCHOLINESTERASE (ACHE) SLOW AND SOMETIMES REVERSE THE COGNITIVE DECLINE EXPERIENCED BY INDIVIDUALS WITH ALZHEIMER'S DISEASE. HUPERZINE A, A NATURAL PRODUCT USED IN TRADITIONAL CHINESE HERBAL MEDICINE, AND TACRINE (COGNEX) ARE AMONG THE POTENT ACHE INHIBITORS USED IN THIS TREATMENT. (-)-12-AMINO-3-CHLORO-9-ETHYL-6,7,10,11-TETRAHYDRO-7,11- METHANOCYCLOOCTA[B]QUINOLINE HYDROCHLORIDE (HUPRINE X), A HYBRID THAT COMBINES THE CARBOBICYCLIC SUBSTRUCTURE OF HUPERZINE A WITH WITH THE 4-AMINOQUINOLINE SUBSTRUCTURE OF TACRINE HUPRINE X BINDS TO HUMAN ACHE WITH AN INHIBITION CONSTANT K(I) OF 26 PM. HUPRINE X SHOWS NO DETECTABLE AFFINITY FOR THE EDROPHONIUM-ACHE COMPLEX. HUPRINE X BINDS TO THE ENZYME ACYLATION SITE IN THE ACTIVE SITE GORGE INTERFERES SLIGHTLY WITH THE BINDING OF PERIPHERAL SITE LIGANDS.

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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: 3.8 Å3/Da / Density % sol: 68 %
Crystal growTemperature: 277 K / pH: 5.6
Details: PROTEIN WAS CRYSTALLISED FROM 35-40% W/V PEG 200 0.3M MES PH 5.6 4 DEG. CELSIUS
Crystal grow
*PLUS
Temperature: 4 ℃ / pH: 6.5 / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
110-11 mg/mlenzyme1drop
21 mMMES1droppH6.5
3100 mM1dropNaCl
40.02 %1dropNaN3
540 %PEG2001reservoir
60.3 MMES1reservoirpH5.8

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Data collection

DiffractionMean temperature: 120 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X12C / Wavelength: 0.98
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Aug 15, 1999 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.1→29.42 Å / Num. obs: 60094 / % possible obs: 76 % / Redundancy: 11.6 % / Biso Wilson estimate: 9.2 Å2 / Rsym value: 0.061 / Net I/σ(I): 16
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 3.52 % / Mean I/σ(I) obs: 2.24 / Rsym value: 0.27 / % possible all: 17.6
Reflection
*PLUS
Num. all: 60094 / Num. obs: 45140 / Num. measured all: 482340 / Rmerge(I) obs: 0.06
Reflection shell
*PLUS
% possible obs: 20 % / Rmerge(I) obs: 0.27 / Mean I/σ(I) obs: 2.2

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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: 2.1→29.42 Å / Rfactor Rfree error: 0.003 / Data cutoff high absF: 2910778.11 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
Details: PROLINE 485 IS OUT OF THE 3FO-2FC DENSITY MAP. THE CONSERVED WATER MOLECULE THAT BELONGS TO THE OXYANION HOLE (HOH 682 IN 2ACE NUMBERING) IS ABSENT IN THIS ENTRY ALTHOUGH A POSITIVE ...Details: PROLINE 485 IS OUT OF THE 3FO-2FC DENSITY MAP. THE CONSERVED WATER MOLECULE THAT BELONGS TO THE OXYANION HOLE (HOH 682 IN 2ACE NUMBERING) IS ABSENT IN THIS ENTRY ALTHOUGH A POSITIVE DIFFERENCE DENSITY HAD BEEN DETECTED IN THAT LOCATION. HERE THIS WATER WAS NOT MODELED BECAUSE OF INSUFICIENT SPACE FOR IT DUE TO MOVEMENT OF SER 200.
RfactorNum. reflection% reflectionSelection details
Rfree0.205 4542 10.1 %RANDOM
Rwork0.177 ---
obs0.177 45083 76 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 70.6596 Å2 / ksol: 0.345552 e/Å3
Displacement parametersBiso mean: 34.4 Å2
Baniso -1Baniso -2Baniso -3
1-6.58 Å24.65 Å20 Å2
2--6.58 Å20 Å2
3----13.17 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.26 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.24 Å0.21 Å
Refinement stepCycle: LAST / Resolution: 2.1→29.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4157 0 49 497 4703
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.012
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_deg1.6
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d23.3
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d1.05
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.191.5
X-RAY DIFFRACTIONc_mcangle_it1.842
X-RAY DIFFRACTIONc_scbond_it5.42
X-RAY DIFFRACTIONc_scangle_it6.872.5
LS refinement shellResolution: 2.1→2.23 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.246 231 10.5 %
Rwork0.235 1967 -
obs--22.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3CARBOHYDRATE.PARAMCARBOHYDRATE.TOP
X-RAY DIFFRACTION4HUP.PARHUP.TOP
Refinement
*PLUS
Highest resolution: 2.1 Å / Lowest resolution: 40 Å / Rfactor obs: 0.176
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg23.3
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.05
LS refinement shell
*PLUS
Rfactor obs: 0.235

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