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- PDB-5i3v: Crystal structure of BACE1 in complex with aminoquinoline compound 1 -

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Basic information

Entry
Database: PDB / ID: 5i3v
TitleCrystal structure of BACE1 in complex with aminoquinoline compound 1
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase Inhibitor / aspartic protease / amyloid precursor protein / Alzheimer's disease / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / hippocampal mossy fiber to CA3 synapse / multivesicular body / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / axon / neuronal cell body / dendrite / Golgi apparatus / enzyme binding / cell surface / proteolysis / membrane / plasma membrane
Similarity search - Function
Beta-secretase BACE1 / Beta-secretase BACE / Memapsin-like / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site ...Beta-secretase BACE1 / Beta-secretase BACE / Memapsin-like / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-68M / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62 Å
AuthorsWhittington, D.A. / Long, A.M.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Fragment-Linking Approach Using (19)F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of beta-Secretase.
Authors: Jordan, J.B. / Whittington, D.A. / Bartberger, M.D. / Sickmier, E.A. / Chen, K. / Cheng, Y. / Judd, T.
History
DepositionFeb 11, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 20, 2016Group: Database references
Revision 1.2May 11, 2016Group: Database references
Revision 1.3Nov 1, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_struct_assembly_auth_evidence / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_special_symmetry
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: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,7006
Polymers45,8221
Non-polymers8775
Water8,179454
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.953, 102.953, 170.381
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-403-

IOD

21A-851-

HOH

31A-905-

HOH

DetailsMonomer by size exclusion chromatography

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Components

#1: Protein Beta-secretase 1 / / Aspartyl protease 2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP ...Aspartyl protease 2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 45822.445 Da / Num. of mol.: 1 / Fragment: UNP residues 43-453 / Mutation: R56K, R57K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-68M / (2R)-3-[2-amino-6-(3-methylpyridin-2-yl)quinolin-3-yl]-N-(3,3-dimethylbutyl)-2-methylpropanamide


Mass: 404.548 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H32N4O
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 454 / 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: 2.84 Å3/Da / Density % sol: 56.76 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.6
Details: 20% polyethylene glycol 5000 MME, 0.2 M ammonium iodide, 0.17 M sodium citrate (pH 6.6), 3% DMSO

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 18, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.62→50 Å / Num. obs: 68266 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 16.1 % / Biso Wilson estimate: 14.3 Å2 / Rmerge(I) obs: 0.067 / Net I/av σ(I): 27 / Net I/σ(I): 21.8
Reflection shell
Resolution (Å)Redundancy (%)Mean I/σ(I) obsDiffraction-ID% possible allRmerge(I) obs
1.62-1.68132.261100
1.68-1.7516.311000.839
1.75-1.8216.511000.575
1.82-1.9216.611000.382
1.92-2.0416.811000.233
2.04-2.216.811000.153
2.2-2.4216.711000.109
2.42-2.7716.711000.077
2.77-3.4916.211000.06
3.49-5015.5199.90.028

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1W50

1w50


Resolution: 1.62→50 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.933 / SU B: 1.669 / SU ML: 0.058 / SU R Cruickshank DPI: 0.0893 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.089 / ESU R Free: 0.088
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2312 3424 5 %RANDOM
Rwork0.2091 ---
obs0.2102 64552 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 77.78 Å2 / Biso mean: 16.294 Å2 / Biso min: 5 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å2-0.02 Å20 Å2
2---0.04 Å20 Å2
3---0.06 Å2
Refinement stepCycle: final / Resolution: 1.62→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2917 0 39 454 3410
Biso mean--14.08 29.87 -
Num. residues----370
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.023031
X-RAY DIFFRACTIONr_bond_other_d0.0010.022036
X-RAY DIFFRACTIONr_angle_refined_deg1.2731.9584120
X-RAY DIFFRACTIONr_angle_other_deg0.8313.0044913
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4315367
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.48623.676136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.91515479
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.1031517
X-RAY DIFFRACTIONr_chiral_restr0.070.2447
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213363
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02645
LS refinement shellResolution: 1.62→1.662 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 220 -
Rwork0.302 4206 -
all-4426 -
obs--95.45 %

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