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- PDB-4zpf: BACE1 in complex with 8-(3-((1-aminopropan-2-yl)oxy)benzyl)-4-(cy... -

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Basic information

Entry
Database: PDB / ID: 4zpf
TitleBACE1 in complex with 8-(3-((1-aminopropan-2-yl)oxy)benzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase inhibitor / Alzheimer Disease / Amyloid Precursor Protein Secretases / Amyloid beta-Peptides / Aspartic Acid Endopeptidases / Binding Sites / Drug Design / Transgenic / Models / Molecular / Protease Inhibitors / Structure-Activity Relationship / 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-4QD / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.8 Å
AuthorsOrth, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Methyl-substitution of an iminohydantoin spiropiperidine beta-secretase (BACE-1) inhibitor has a profound effect on its potency.
Authors: Egbertson, M. / McGaughey, G.B. / Pitzenberger, S.M. / Stauffer, S.R. / Coburn, C.A. / Stachel, S.J. / Yang, W. / Barrow, J.C. / Neilson, L.A. / McWherter, M. / Perlow, D. / Fahr, B. / ...Authors: Egbertson, M. / McGaughey, G.B. / Pitzenberger, S.M. / Stauffer, S.R. / Coburn, C.A. / Stachel, S.J. / Yang, W. / Barrow, J.C. / Neilson, L.A. / McWherter, M. / Perlow, D. / Fahr, B. / Munshi, S. / Allison, T.J. / Holloway, K. / Selnick, H.G. / Yang, Z. / Swestock, J. / Simon, A.J. / Sankaranarayanan, S. / Colussi, D. / Tugusheva, K. / Lai, M.T. / Pietrak, B. / Haugabook, S. / Jin, L. / Chen, I.W. / Holahan, M. / Stranieri-Michener, M. / Cook, J.J. / Vacca, J. / Graham, S.L.
History
DepositionMay 7, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 5, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 28, 2015Group: Database references

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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)45,6302
Polymers45,1231
Non-polymers5081
Water4,864270
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15780 Å2
Unit cell
Length a, b, c (Å)103.720, 127.403, 77.024
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-841-

HOH

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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: 45122.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Plasmid: pet11a / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-4QD / 8-(3-{[(2S)-1-aminopropan-2-yl]oxy}benzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one


Mass: 507.643 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H38FN5O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 270 / 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: 3.08 Å3/Da / Density % sol: 60.08 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 1.5M LITHIUM SULFATE, 0.1M HEPES BUFFER,

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jan 5, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 47532 / % possible obs: 99.9 % / Redundancy: 9.6 % / Rmerge(I) obs: 0.079 / Χ2: 1.304 / Net I/av σ(I): 28.538 / Net I/σ(I): 15.3 / Num. measured all: 454732
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.8-1.867.90.8371.746920.918199.9
1.86-1.948.30.632.346960.95399.8
1.94-2.039.30.4353.846990.965100
2.03-2.139.70.3175.447141.03299.9
2.13-2.279.60.2257.847371.1199.9
2.27-2.4410.20.1710.847221.12100
2.44-2.6910.20.1215.847251.221100
2.69-3.0810.30.08525.547801.42100
3.08-3.8810.10.05546.348071.92499.9
3.88-50100.04365.449602.11799.7

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Processing

Software
NameVersionClassification
BUSTER-TNT2.11.4refinement
DENZOdata reduction
PDB_EXTRACT3.1data extraction
SCALEPACKdata scaling
RefinementResolution: 1.8→26.35 Å / Cor.coef. Fo:Fc: 0.9444 / Cor.coef. Fo:Fc free: 0.9409 / Occupancy max: 1 / Occupancy min: 0.5 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2012 1868 3.93 %RANDOM
Rwork0.1813 ---
obs0.1821 47472 99.81 %-
Displacement parametersBiso max: 112.94 Å2 / Biso mean: 33.9503 Å2 / Biso min: 16.17 Å2
Baniso -1Baniso -2Baniso -3
1-3.0364 Å20 Å20 Å2
2---10.1036 Å20 Å2
3---7.0672 Å2
Refine analyzeLuzzati coordinate error obs: 0.192 Å
Refinement stepCycle: LAST / Resolution: 1.8→26.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2874 0 37 270 3181
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d972SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes67HARMONIC2
X-RAY DIFFRACTIONt_gen_planes446HARMONIC5
X-RAY DIFFRACTIONt_it2993HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion384SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3302SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2993HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4080HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion3.87
X-RAY DIFFRACTIONt_other_torsion14.97
LS refinement shellResolution: 1.8→1.85 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2858 142 4.13 %
Rwork0.2583 3299 -
all0.2594 3441 -
obs--99.81 %

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