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- PDB-4rcf: Crystal structure of BACE1 in complex with 2-aminooxazoline 4-flu... -

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Basic information

Entry
Database: PDB / ID: 4rcf
TitleCrystal structure of BACE1 in complex with 2-aminooxazoline 4-fluoroxanthene inhibitor 49
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase inhibitor / aspartic protease / Alzheimer's disease / APP / amyloid precursor protein / brain / 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 / protein serine/threonine kinase binding / 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 / protein processing / recycling endosome / 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 / aspartic-type endopeptidase activity / lysosome / 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-3LO / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsWhittington, D.A. / Long, A.M.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors.
Authors: Epstein, O. / Bryan, M.C. / Cheng, A.C. / Derakhchan, K. / Dineen, T.A. / Hickman, D. / Hua, Z. / Human, J.B. / Kreiman, C. / Marx, I.E. / Weiss, M.M. / Wahl, R.C. / Wen, P.H. / Whittington, ...Authors: Epstein, O. / Bryan, M.C. / Cheng, A.C. / Derakhchan, K. / Dineen, T.A. / Hickman, D. / Hua, Z. / Human, J.B. / Kreiman, C. / Marx, I.E. / Weiss, M.M. / Wahl, R.C. / Wen, P.H. / Whittington, D.A. / Wood, S. / Zheng, X.M. / Fremeau, R.T. / White, R.D. / Patel, V.F.
History
DepositionSep 15, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 24, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 14, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software

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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)46,7436
Polymers45,8221
Non-polymers9205
Water6,215345
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.262, 102.262, 170.306
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-653-

HOH

31A-815-

HOH

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Components

#1: Protein Beta-secretase 1 / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta- ...Aspartyl protease 2 / ASP2 / 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: catalytic domain (UNP residues 43-453) / Mutation: R(-5)K, R(-4)K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-3LO / (4S)-2'-(3,6-dihydro-2H-pyran-4-yl)-4'-fluoro-7'-(2-fluoropyridin-3-yl)spiro[1,3-oxazole-4,9'-xanthen]-2-amine


Mass: 447.433 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H19F2N3O3
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 345 / 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: 2.8 Å3/Da / Density % sol: 56.15 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.6
Details: 21% polyethylene glycol 5000 monomethyl ether, 200 mM ammonium iodide, 180 mM sodium citrate, pH 6.6, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 8, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 1.78→50 Å / Num. all: 51125 / Num. obs: 51023 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 14.2 % / Biso Wilson estimate: 25.6 Å2 / Rmerge(I) obs: 0.078 / Χ2: 1.041 / Net I/σ(I): 24.8
Reflection shell
Resolution (Å)Redundancy (%)Num. unique allΧ2Diffraction-ID% possible allRmerge(I) obs
1.78-1.8414.249650.757199.6
1.84-1.9214.250070.802199.60.734
1.92-214.450200.838199.70.481
2-2.1114.450040.874199.80.328
2.11-2.2414.550450.905199.90.226
2.24-2.4214.550550.913199.90.163
2.42-2.6614.450920.91711000.113
2.66-3.0414.351421.06411000.077
3.04-3.8313.951952.12911000.064
3.83-5013.354981.211199.60.032

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.78→50 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.943 / WRfactor Rfree: 0.2136 / WRfactor Rwork: 0.1899 / FOM work R set: 0.8505 / SU B: 2.4 / SU ML: 0.076 / SU R Cruickshank DPI: 0.1126 / SU Rfree: 0.1084 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.113 / ESU R Free: 0.108 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2289 2592 5.1 %RANDOM
Rwork0.2026 ---
obs0.2039 50970 99.83 %-
all-51007 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 88.36 Å2 / Biso mean: 26.221 Å2 / Biso min: 13.28 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å2-0.01 Å20 Å2
2---0.01 Å20 Å2
3---0.02 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.108 Å0.113 Å
Refinement stepCycle: LAST / Resolution: 1.78→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2917 0 42 345 3304
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.023037
X-RAY DIFFRACTIONr_bond_other_d0.0010.022041
X-RAY DIFFRACTIONr_angle_refined_deg1.2251.9634131
X-RAY DIFFRACTIONr_angle_other_deg0.8183.0044919
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.245367
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.29823.676136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.84715479
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7181517
X-RAY DIFFRACTIONr_chiral_restr0.070.2446
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213374
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02647
LS refinement shellResolution: 1.78→1.826 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.289 193 -
Rwork0.31 3191 -
all-3384 -
obs--99.62 %

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