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Basic information

Entry
Database: PDB / ID: 4i0j
TitleSPR and structural analysis yield insight towards mechanism of inhibition of BACE inhibitors
ComponentsBeta-secretase 1
Keywordshydrolase/hydrolase inhibitor / BACE Asp protease / hydrolysis / 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 / aspartic-type endopeptidase activity / lysosome / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / 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-842 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsYao, N. / Brecht, E.
CitationJournal: TO BE PUBLISHED
Title: SPR and structural analysis yield insight towards mechanism of inhibition of BACE inhibitors
Authors: Mondal, K. / Regnstrom, K. / Morishige, W. / Barbour, R. / Beroza, P. / Yao, N. / Bova, M.P.
History
DepositionNov 16, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release

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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)46,1896
Polymers45,4451
Non-polymers7445
Water4,053225
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Beta-secretase 1
hetero molecules

A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,37912
Polymers90,8902
Non-polymers1,48810
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area1580 Å2
ΔGint-246 kcal/mol
Surface area33530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.228, 104.039, 99.063
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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: 45445.121 Da / Num. of mol.: 1 / Fragment: unp residues 57-453
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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-842 / N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(1H-pyrazol-1-yl)phenyl]cyclohexyl}amino)propyl]acetamide


Mass: 482.565 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32F2N4O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 225 / 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: 2.13 Å3/Da / Density % sol: 42.32 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.3
Details: BACE was concentrated to 10mg/ml in 100 mM borate pH 8.5. Apo crystals were grown at 277K in 1 uL with a 1:1(v/v) ratio of protein to reservoir, a solution of 9% PEG 8000, 100mM sodium ...Details: BACE was concentrated to 10mg/ml in 100 mM borate pH 8.5. Apo crystals were grown at 277K in 1 uL with a 1:1(v/v) ratio of protein to reservoir, a solution of 9% PEG 8000, 100mM sodium acetate and 10mM ZnCl2 , VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Jan 1, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→60 Å / Num. all: 36259 / Num. obs: 39466 / % possible obs: 92 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1

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Processing

Software
NameVersionClassification
StructureStudiodata collection
MOLREPphasing
REFMAC5.5.0102refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.99→60 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.921 / SU B: 6.92 / SU ML: 0.189 / Cross valid method: THROUGHOUT / ESU R: 0.25 / ESU R Free: 0.222 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29481 1305 5 %RANDOM
Rwork0.22572 ---
obs0.22921 24728 96.22 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.477 Å2
Baniso -1Baniso -2Baniso -3
1--1.23 Å20 Å20 Å2
2---1.93 Å20 Å2
3---3.15 Å2
Refinement stepCycle: LAST / Resolution: 1.99→60 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3063 0 39 225 3327
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0223184
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8591.9524328
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7515385
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.77223.673147
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.06315500
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3691518
X-RAY DIFFRACTIONr_chiral_restr0.1260.2465
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212448
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0571.51923
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.84523110
X-RAY DIFFRACTIONr_scbond_it2.86931261
X-RAY DIFFRACTIONr_scangle_it4.3634.51218
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.989→2.041 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.391 80 -
Rwork0.356 1690 -
obs--89.71 %

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