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- PDB-5i3x: Crystal structure of BACE1 in complex with aminoquinoline inhibitor 6 -

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Basic information

Entry
Database: PDB / ID: 5i3x
TitleCrystal structure of BACE1 in complex with aminoquinoline inhibitor 6
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE Inhibitor / aspartic protease / Alzheimer's disease / APP / amyloid precursor protein / HYDROLASE-HYDROLASE Inhibitor complex
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to manganese ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / recycling endosome / protein processing / response to lead ion / cellular response to amyloid-beta / synaptic vesicle / late endosome / peptidase activity / positive regulation of neuron apoptotic process / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / endosome / endosome membrane / membrane raft / endoplasmic reticulum lumen / Amyloid fiber formation / axon / neuronal cell body / dendrite / enzyme binding / cell surface / Golgi apparatus / 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-68J / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 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 / 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 1.5Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5053
Polymers45,8221
Non-polymers6832
Water7,800433
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)101.590, 101.590, 174.626
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
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-68J / N-(1-{3-[2-(2-amino-3-{3-[(3,3-dimethylbutyl)amino]-3-oxopropyl}quinolin-6-yl)phenyl]prop-2-yn-1-yl}cyclopropyl)-4-fluorobenzamide


Mass: 590.730 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H39FN4O2
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 433 / Source method: isolated from a natural source / Formula: H2O
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: 2.84 Å3/Da / Density % sol: 56.67 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6
Details: 1.5 M ammonium sulfate, 0.2 M lithium chloride, 0.1 M MES (pH 6.0)
PH range: 5.5-6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jul 11, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 46126 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 7.2 % / Biso Wilson estimate: 19.2 Å2 / Rmerge(I) obs: 0.113 / Net I/av σ(I): 16.3 / Net I/σ(I): 11.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.85-1.927.20.8012.29199.6
1.92-1.997.30.537199.6
1.99-2.087.30.38199.8
2.08-2.197.30.278199.8
2.19-2.337.30.21199.9
2.33-2.517.30.171100
2.51-2.767.30.1271100
2.76-3.167.20.0951100
3.16-3.997.10.0811100
3.99-506.80.048199.8

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Processing

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

1w50


Resolution: 1.85→50 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.937 / SU B: 2.307 / SU ML: 0.07 / SU R Cruickshank DPI: 0.1122 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.112 / ESU R Free: 0.112
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2124 2318 5 %RANDOM
Rwork0.1763 ---
obs0.1781 43690 99.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 71.72 Å2 / Biso mean: 19.29 Å2 / Biso min: 2.97 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20.03 Å20 Å2
2--0.06 Å20 Å2
3----0.09 Å2
Refinement stepCycle: final / Resolution: 1.85→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2937 0 50 433 3420
Biso mean--20.03 33.01 -
Num. residues----373
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.023068
X-RAY DIFFRACTIONr_bond_other_d0.0010.022058
X-RAY DIFFRACTIONr_angle_refined_deg1.2581.9634174
X-RAY DIFFRACTIONr_angle_other_deg0.8123.0054950
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6135370
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.40923.768138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.35915478
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8721517
X-RAY DIFFRACTIONr_chiral_restr0.0760.2450
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213408
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02648
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.365 151 -
Rwork0.289 2859 -
all-3010 -
obs--97.79 %

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