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- PDB-4hzt: Structure-based design of novel dihydroisoquinoline BACE-1 inhibi... -

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Basic information

Entry
Database: PDB / ID: 4hzt
TitleStructure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates
ComponentsBeta-secretase 1
Keywordshydrolase/hydrolase inhibitor / Aspartic 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 / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain ...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 / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / 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 / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / 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-0ZA / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsYao, N. / Brecht, E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.
Authors: Bowers, S. / Xu, Y.Z. / Yuan, S. / Probst, G.D. / Hom, R.K. / Chan, W. / Konradi, A.W. / Sham, H.L. / Zhu, Y.L. / Beroza, P. / Pan, H. / Brecht, E. / Yao, N. / Lougheed, J. / Tam, D. / Ren, ...Authors: Bowers, S. / Xu, Y.Z. / Yuan, S. / Probst, G.D. / Hom, R.K. / Chan, W. / Konradi, A.W. / Sham, H.L. / Zhu, Y.L. / Beroza, P. / Pan, H. / Brecht, E. / Yao, N. / Lougheed, J. / Tam, D. / Ren, Z. / Ruslim, L. / Bova, M.P. / Artis, D.R.
History
DepositionNov 15, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2013Group: 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)46,0385
Polymers45,4451
Non-polymers5934
Water7,170398
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)92,07610
Polymers90,8902
Non-polymers1,1868
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555-x,y,-z+1/21
Buried area1740 Å2
ΔGint-189 kcal/mol
Surface area33940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.256, 103.972, 100.302
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-649-

HOH

21A-798-

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: 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.: 3 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-0ZA / 3-{(1S)-1-[(6-chloro-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)amino]-2-phenylethyl}-1,2,4-oxadiazol-5(2H)-one


Mass: 396.870 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21ClN4O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 398 / 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: 2.16 Å3/Da / Density % sol: 43.02 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 5.3
Details: BACE was concentrated to 10mg/ml in 100 mM borate pH 8.5, 9% PEG 8000, 100mM Sodium Acetate and 10mM ZnCl2, VAPOR DIFFUSION, temperature 277K

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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: May 31, 2011
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: 36789 / Num. obs: 32259 / % possible obs: 88 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.5.0109refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→60 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.93 / SU B: 3.233 / SU ML: 0.102 / Cross valid method: THROUGHOUT / ESU R: 0.175 / ESU R Free: 0.167 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25636 1614 5 %RANDOM
Rwork0.19758 ---
obs0.20065 30577 87.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.957 Å2
Baniso -1Baniso -2Baniso -3
1--0.3 Å20 Å20 Å2
2---0.85 Å20 Å2
3---1.14 Å2
Refinement stepCycle: LAST / Resolution: 1.8→60 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3099 0 31 398 3528
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.0223214
X-RAY DIFFRACTIONr_angle_refined_deg1.9371.954373
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9515391
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.33323.758149
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.21215505
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5751518
X-RAY DIFFRACTIONr_chiral_restr0.1530.2470
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0212480
X-RAY DIFFRACTIONr_mcbond_it1.3331.51949
X-RAY DIFFRACTIONr_mcangle_it2.24423154
X-RAY DIFFRACTIONr_scbond_it3.17131265
X-RAY DIFFRACTIONr_scangle_it4.9684.51219
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.472 59 -
Rwork0.398 1050 -
obs--41.43 %

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