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- PDB-3ivh: Design and Synthesis of Potent BACE-1 Inhibitors with Cellular Ac... -

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Basic information

Entry
Database: PDB / ID: 3ivh
TitleDesign and Synthesis of Potent BACE-1 Inhibitors with Cellular Activity: Structure-Activity Relationship of P1 Substituents
ComponentsBeta-secretase 1
KeywordsHYDROLASE / aspartyl protease / BACE-1 inhibitors / Alzheimer's disease / structure-based drug design / Disulfide bond / Glycoprotein / Membrane / Protease / Transmembrane / Zymogen
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 / amyloid-beta metabolic process ...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 / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / 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-1LI / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsPan, H.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents.
Authors: Sealy, J.M. / Truong, A.P. / Tso, L. / Probst, G.D. / Aquino, J. / Hom, R.K. / Jagodzinska, B.M. / Dressen, D. / Wone, D.W. / Brogley, L. / John, V. / Tung, J.S. / Pleiss, M.A. / Tucker, J.A. ...Authors: Sealy, J.M. / Truong, A.P. / Tso, L. / Probst, G.D. / Aquino, J. / Hom, R.K. / Jagodzinska, B.M. / Dressen, D. / Wone, D.W. / Brogley, L. / John, V. / Tung, J.S. / Pleiss, M.A. / Tucker, J.A. / Konradi, A.W. / Dappen, M.S. / Toth, G. / Pan, H. / Ruslim, L. / Miller, J. / Bova, M.P. / Sinha, S. / Quinn, K.P. / Sauer, J.M.
History
DepositionSep 1, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 5, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance

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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)45,9182
Polymers45,4451
Non-polymers4731
Water4,486249
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.924, 105.181, 51.029
Angle α, β, γ (deg.)90.000, 95.250, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Beta-secretase 1 / / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Membrane- ...Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Membrane-associated aspartic protease 2 / Memapsin-2 / Aspartyl protease 2 / Asp 2 / ASP2


Mass: 45445.121 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Plasmid: pQE70 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-1LI / N-[(1S,2R)-3-{[1-(3-tert-butylphenyl)cyclohexyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide


Mass: 472.610 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H38F2N2O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 249 / 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: 2.14 Å3/Da / Density % sol: 42.63 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 4.5
Details: 0.1 M sodium acetate pH 4.5, 20% PEG200 Compound was added to give a final molar access of compound:protein of 2.5:1, VAPOR DIFFUSION, SITTING DROP, temperature 289K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11587
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 13, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11587 Å / Relative weight: 1
ReflectionHighest resolution: 1.8 Å / Num. all: 32729 / Num. obs: 30386
Reflection shellResolution: 1.8→1.847 Å

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALAdata scaling
MOLREPphasing
TNTrefinement
PDB_EXTRACT3.005data extraction
HKL-2000data collection
MOSFLMdata reduction
AMoREphasing
REFMAC5.1.25refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.926 / Highest resolution: 1.8 Å / Occupancy max: 1 / Occupancy min: 1 / SU B: 4.419 / SU ML: 0.128 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.168 / ESU R Free: 0.153 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.249 1596 5 %RANDOM
Rwork0.206 ---
obs0.208 30386 92.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 55.1 Å2 / Biso mean: 23.803 Å2 / Biso min: 10.32 Å2
Baniso -1Baniso -2Baniso -3
1--1.95 Å20 Å2-0.54 Å2
2--0.61 Å20 Å2
3---1.24 Å2
Refinement stepCycle: LAST / Highest resolution: 1.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2980 0 34 249 3263
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.304 127
Rwork0.266 2323
all-2450
Refinement TLS params.Method: refined / Origin x: 15.899 Å / Origin y: -0.196 Å / Origin z: 10.132 Å
111213212223313233
T0.0773 Å20.009 Å20.018 Å2-0.0775 Å20.0008 Å2--0.0042 Å2
L2.0064 °21.1264 °20.5428 °2-1.3624 °20.503 °2--0.2533 °2
S0.0894 Å °0.0401 Å °-0.0534 Å °0.1492 Å °-0.0437 Å °0.0165 Å °0.0244 Å °-0.0214 Å °-0.0458 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A59 - 219
2X-RAY DIFFRACTION1A224 - 372
3X-RAY DIFFRACTION1A379 - 447

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