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- PDB-3k5f: Human BACE-1 COMPLEX WITH AYH011 -

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Basic information

Entry
Database: PDB / ID: 3k5f
TitleHuman BACE-1 COMPLEX WITH AYH011
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / aspartyl protease / alzheimer's disease / structure-based design / Disulfide bond / Endoplasmic reticulum / Endosome / Glycoprotein / Golgi apparatus / Hydrolase-Hydrolase inhibitor complex / Membrane / Protease / Transmembrane
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-AYH / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.25 Å
AuthorsRondeau, J.-M.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Structure-based design and synthesis of novel P2/P3 modified, non-peptidic beta-secretase (BACE-1) inhibitors.
Authors: Hanessian, S. / Shao, Z. / Betschart, C. / Rondeau, J.M. / Neumann, U. / Tintelnot-Blomley, M.
#1: Journal: Bioorg. Med. Chem. Lett. / Year: 2009
Title: Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors
Authors: Machauer, R. / Veenstra, S. / Rondeau, J.-M. / Tintelnot-Blomley, M. / Betschart, C. / Neumann, U. / Paganetti, P.
#2: Journal: Bioorg. Med. Chem. Lett. / Year: 2009
Title: Macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors with activity in vivo
Authors: Machauer, R. / Laumen, K. / Veenstra, S. / Rondeau, J.-M. / Tintelnot-Blomley, M. / Betschart, C. / Jaton, A.-L. / Desrayaud, S. / Staufenbiel, M. / Rabe, S. / Paganetti, P. / Neumann, U.
History
DepositionOct 7, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 5, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Nov 1, 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)135,8376
Polymers134,3323
Non-polymers1,5053
Water8,935496
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2792
Polymers44,7771
Non-polymers5021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2792
Polymers44,7771
Non-polymers5021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2792
Polymers44,7771
Non-polymers5021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.651, 103.708, 101.818
Angle α, β, γ (deg.)90.000, 102.530, 90.000
Int Tables number4
Space group name H-MP1211
DetailsThe biological unit is a monomer. There are 3 biological units in the asymmetric unit (chains A, B and C)

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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: 44777.336 Da / Num. of mol.: 3 / Fragment: Catalytic domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Plasmid: pET24 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 TUNER (DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-AYH / (1R,3S)-3-[1-(acetylamino)-1-methylethyl]-N-[(1S,2S,4R)-1-benzyl-5-(butylamino)-2-hydroxy-4-methyl-5-oxopentyl]cyclohexanecarboxamide / (1R,3S)-3-(1-Acetylamino-1-methyl-ethyl)-cyclohexanecarboxylic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide


Mass: 501.701 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C29H47N3O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 496 / 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: 3.17 Å3/Da / Density % sol: 61.21 %
Crystal growTemperature: 292 K / Method: vapor diffusion / pH: 5.5
Details: CRYSTALS WERE GROWN AT 19C BY VAPOUR DIFFUSION IN HANGING DROPS FROM 1.0M AMMONIUM SULFATE. PROTEIN STOCK WAS 8.45MG/ML BACE IN 10MM TRIS-HCL PH 7.4, 25MM NACL, WITH A 2-FOLD EXCESS OF ...Details: CRYSTALS WERE GROWN AT 19C BY VAPOUR DIFFUSION IN HANGING DROPS FROM 1.0M AMMONIUM SULFATE. PROTEIN STOCK WAS 8.45MG/ML BACE IN 10MM TRIS-HCL PH 7.4, 25MM NACL, WITH A 2-FOLD EXCESS OF INHIBITOR ADDED FROM A 10MM STOCK SOLUTION IN DMSO (4% DMSO IN DROP).CRYO-PROTECTANT WAS 22%(V/V) GLYCEROL, 78% (V/V) RESERVOIR SOLUTION., VAPOR DIFFUSION, temperature 292K

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Data collection

DiffractionMean temperature: 105 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.97936 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Sep 2, 2004 / Details: Mirrors
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97936 Å / Relative weight: 1
ReflectionResolution: 2.25→100 Å / Num. all: 74108 / Num. obs: 74108 / % possible obs: 93.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.1 % / Biso Wilson estimate: 48.1 Å2 / Rmerge(I) obs: 0.068 / Rsym value: 0.068 / Χ2: 1.045 / Net I/σ(I): 9.1
Reflection shellResolution: 2.25→2.33 Å / Rmerge(I) obs: 0.355 / Num. unique all: 5653 / Rsym value: 0.355 / Χ2: 0.404 / % possible all: 72

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3.005data extraction
CNXphasing
CNXrefinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.25→43.62 Å / Rfactor Rfree error: 0.004 / Occupancy max: 1 / Occupancy min: 1 / Data cutoff high absF: 17583808 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.232 3718 5.1 %RANDOM
Rwork0.209 ---
all0.215 74108 --
obs0.212 72802 91.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 46.257 Å2 / ksol: 0.345 e/Å3
Displacement parametersBiso max: 112.74 Å2 / Biso mean: 46.911 Å2 / Biso min: 20.88 Å2
Baniso -1Baniso -2Baniso -3
1--2.77 Å20 Å2-7.16 Å2
2--6.01 Å20 Å2
3----3.24 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.31 Å0.27 Å
Luzzati d res low-5 Å
Luzzati sigma a0.25 Å0.21 Å
Refinement stepCycle: LAST / Resolution: 2.25→43.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8860 0 108 496 9464
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d24.8
X-RAY DIFFRACTIONc_improper_angle_d0.77
X-RAY DIFFRACTIONc_mcbond_it1.981.5
X-RAY DIFFRACTIONc_mcangle_it3.112
X-RAY DIFFRACTIONc_scbond_it2.872
X-RAY DIFFRACTIONc_scangle_it42.5
LS refinement shellResolution: 2.25→2.39 Å / Rfactor Rfree error: 0.015 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.332 469 5.2 %
Rwork0.282 8564 -
all-9033 -
obs-8564 68.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3NVP-AYH011.PRMION.TOP

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