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- PDB-4lxm: Crystal Structure of Human Beta Secretase in Complex with compound 12a -

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Basic information

Entry
Database: PDB / ID: 4lxm
TitleCrystal Structure of Human Beta Secretase in Complex with compound 12a
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Structure-based drug design / Aspartyl protease / Membrane / 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 / 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 / dendrite / neuronal cell body / 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-1YU / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 Å
AuthorsRondeau, J.M. / Bourgier, E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides.
Authors: Rueeger, H. / Lueoend, R. / Machauer, R. / Veenstra, S.J. / Jacobson, L.H. / Staufenbiel, M. / Desrayaud, S. / Rondeau, J.M. / Mobitz, H. / Neumann, U.
History
DepositionJul 30, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2013Group: Other
Revision 1.2Nov 20, 2013Group: Database references
Revision 1.3Nov 15, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)136,0866
Polymers134,3323
Non-polymers1,7543
Water9,566531
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3622
Polymers44,7771
Non-polymers5851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3622
Polymers44,7771
Non-polymers5851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3622
Polymers44,7771
Non-polymers5851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.290, 104.447, 100.487
Angle α, β, γ (deg.)90.00, 104.30, 90.00
Int Tables number4
Space group name H-MP1211

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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: 44777.336 Da / Num. of mol.: 3 / Fragment: Catalytic domain, UNP residues 48-447
Source method: isolated from a genetically manipulated source
Details: Refolded / Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Plasmid: pET24 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-1YU / (1S,3S,4S,5R)-3-{4-amino-3-fluoro-5-[(1,1,1,3,3,3-hexafluoropropan-2-yl)oxy]benzyl}-5-[(3-tert-butylbenzyl)amino]tetrahydro-2H-thiopyran-4-ol 1-oxide


Mass: 584.590 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C26H31F7N2O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 531 / 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: 3.12 Å3/Da / Density % sol: 60.51 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 1.0M ammonium sulfate in water, pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.9993 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Apr 9, 2008 / Details: mirrors
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9993 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 73261 / Num. obs: 73261 / % possible obs: 99.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 14.8 % / Biso Wilson estimate: 47.3 Å2 / Rmerge(I) obs: 0.088 / Χ2: 0.982 / Net I/σ(I): 7.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.3-2.3814.20.45172650.606199.2
2.38-2.4814.40.31172480.372199.5
2.48-2.5914.60.23873400.427199.8
2.59-2.7314.80.19273100.491199.9
2.73-2.9150.1573700.6181100
2.9-3.1215.30.11973250.8381100
3.12-3.4415.40.09973941.1771100
3.44-3.9315.30.08873431.7921100
3.93-4.9515.20.0773951.9361100
4.95-5013.80.05572711.483196.9

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
CNX2002phasing
CNX2002refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.3→16.67 Å / Rfactor Rfree error: 0.004 / Occupancy max: 1 / Occupancy min: 0.5 / Data cutoff high absF: 16487693 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.218 3719 5.1 %RANDOM
Rwork0.194 ---
all0.196 72839 --
obs0.196 72839 99.7 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 48.1898 Å2 / ksol: 0.3574 e/Å3
Displacement parametersBiso max: 119.59 Å2 / Biso mean: 47.6596 Å2 / Biso min: 22.2 Å2
Baniso -1Baniso -2Baniso -3
1--4.06 Å20 Å2-3.18 Å2
2--11.21 Å20 Å2
3----7.15 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.3 Å0.26 Å
Luzzati d res low-5 Å
Luzzati sigma a0.27 Å0.21 Å
Refinement stepCycle: LAST / Resolution: 2.3→16.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8925 0 117 531 9573
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_dihedral_angle_d23.9
X-RAY DIFFRACTIONc_improper_angle_d0.66
X-RAY DIFFRACTIONc_mcbond_it1.521.5
X-RAY DIFFRACTIONc_mcangle_it2.572
X-RAY DIFFRACTIONc_scbond_it2.042
X-RAY DIFFRACTIONc_scangle_it3.072.5
LS refinement shellResolution: 2.3→2.44 Å / Rfactor Rfree error: 0.011 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.278 615 5.1 %
Rwork0.241 11419 -
all-12034 -
obs-12034 99.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3cis_peptide.paramcompound_12a_equa.top
X-RAY DIFFRACTION4compound_12a_equa.paramion.top
X-RAY DIFFRACTION5ion.param

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