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- PDB-5i3y: Crystal structure of BACE1 in complex with aminoquinoline inhibitor 9 -

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Basic information

Entry
Database: PDB / ID: 5i3y
TitleCrystal structure of BACE1 in complex with aminoquinoline inhibitor 9
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 / 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-68K / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 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 1.5Nov 20, 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)46,4402
Polymers45,8221
Non-polymers6181
Water3,981221
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)102.788, 102.788, 170.300
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-684-

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-68K / N-(6-{2-[2-(2-amino-3-{3-[(3,3-dimethylbutyl)amino]-3-oxopropyl}quinolin-6-yl)phenyl]ethyl}pyridin-3-yl)-4-fluorobenzamide


Mass: 617.755 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H40FN5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 221 / 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: 2.83 Å3/Da / Density % sol: 56.6 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 5.5
Details: 1.5 M ammonium sulfate, 0.2 M lithium chloride, 0.1 M bis-tris (pH 5.5)
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: 2.15→50 Å / Num. obs: 29605 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 10.8 % / Biso Wilson estimate: 26.2 Å2 / Rmerge(I) obs: 0.135 / Net I/av σ(I): 15.3 / Net I/σ(I): 14.3
Reflection shell
Resolution (Å)Redundancy (%)Mean I/σ(I) obsDiffraction-ID% possible allRmerge(I) obs
2.15-2.2310.92.151100
2.23-2.3210.911000.887
2.32-2.4210.911000.715
2.42-2.5510.911000.555
2.55-2.7110.811000.418
2.71-2.9210.911000.286
2.92-3.2110.811000.184
3.21-3.6810.811000.106
3.68-4.6310.7199.70.062
4.63-5010.1198.70.04

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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: 2.15→50 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.919 / SU B: 8.99 / SU ML: 0.13 / SU R Cruickshank DPI: 0.2001 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.2 / ESU R Free: 0.176
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2377 1462 5 %RANDOM
Rwork0.1995 ---
obs0.2014 27922 99.19 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 225.41 Å2 / Biso mean: 40.743 Å2 / Biso min: 8.95 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å2-0.03 Å20 Å2
2---0.05 Å20 Å2
3---0.08 Å2
Refinement stepCycle: final / Resolution: 2.15→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2913 0 46 221 3180
Biso mean--19.75 32.51 -
Num. residues----369
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.023039
X-RAY DIFFRACTIONr_bond_other_d0.0010.022040
X-RAY DIFFRACTIONr_angle_refined_deg1.2521.9634131
X-RAY DIFFRACTIONr_angle_other_deg0.8233.0054903
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.785365
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.29623.723137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.7915478
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5441517
X-RAY DIFFRACTIONr_chiral_restr0.070.2444
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213374
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02644
LS refinement shellResolution: 2.151→2.207 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.311 92 -
Rwork0.26 1797 -
all-1889 -
obs--92.28 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
16.963-0.5023-2.46892.48510.63513.3227-0.44150.3361-0.73030.0431-0.01740.12320.4107-0.17160.45890.091-0.02780.08620.056-0.05420.109519.30228.304-6.6395
28.8316-3.7484-3.38473.9481.06363.71690.48990.51131.1931-0.1946-0.1321-0.5384-0.3478-0.2637-0.35790.07430.01260.07850.09180.05680.17516.270447.45171.9794
38.234-4.2866-3.89475.05770.54213.74450.7817-0.52613.4868-0.33120.1977-2.8866-0.64110.671-0.97940.209-0.05850.29510.2274-0.14481.895315.346757.86395.7073
49.5006-5.5938-3.32895.03231.00341.77940.1496-0.02471.0644-0.09210.1265-0.7639-0.1381-0.0075-0.27610.1336-0.02680.02340.05850.00340.14885.505247.21635.9807
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-1 - 145
2X-RAY DIFFRACTION2A146 - 251
3X-RAY DIFFRACTION3A252 - 321
4X-RAY DIFFRACTION4A322 - 385

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