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- PDB-3k5c: Human BACE-1 complex with NB-216 -

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Basic information

Entry
Database: PDB / ID: 3k5c
TitleHuman BACE-1 complex with NB-216
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / aspartyl proteinase / alzheimer's disease / Aspartyl protease / 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-0BI / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.12 Å
AuthorsRondeau, J.-M.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Macrocyclic BACE-1 inhibitors acutely reduce Abeta in brain after po application.
Authors: Lerchner, A. / Machauer, R. / Betschart, C. / Veenstra, S. / Rueeger, H. / McCarthy, C. / Tintelnot-Blomley, M. / Jaton, A.L. / Rabe, S. / Desrayaud, S. / Enz, A. / Staufenbiel, M. / ...Authors: Lerchner, A. / Machauer, R. / Betschart, C. / Veenstra, S. / Rueeger, H. / McCarthy, C. / Tintelnot-Blomley, M. / Jaton, A.L. / Rabe, S. / Desrayaud, S. / Enz, A. / Staufenbiel, M. / Paganetti, P. / Rondeau, J.M. / Neumann, U.
#1: 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 1.0Mar 2, 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

Downloads & links

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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)136,0476
Polymers134,3323
Non-polymers1,7153
Water8,431468
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3492
Polymers44,7771
Non-polymers5721
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3492
Polymers44,7771
Non-polymers5721
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3492
Polymers44,7771
Non-polymers5721
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.752, 103.186, 100.144
Angle α, β, γ (deg.)90.000, 104.440, 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-0BI / (4S)-4-[(1R)-1-hydroxy-2-({1-[3-(1-methylethyl)phenyl]cyclopropyl}amino)ethyl]-19-(methoxymethyl)-11-oxa-3,16-diazatricyclo[15.3.1.1~6,10~]docosa-1(21),6(22),7,9,17,19-hexaen-2-one / (S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-19-methoxymethyl-11-oxa 3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17 ,19-hexaen-2-one


Mass: 571.749 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C35H45N3O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 468 / 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: 3.05 Å3/Da / Density % sol: 59.61 %
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 IN WATER. PROTEIN STOCK WAS BACE1 7.0MG/ML IN 10MM TRIS-HCL PH 7.4, 25MM NACL, WITH A 6-FOLD EXCESS ...Details: CRYSTALS WERE GROWN AT 19C BY VAPOUR DIFFUSION IN HANGING DROPS FROM 1.0M AMMONIUM SULFATE IN WATER. PROTEIN STOCK WAS BACE1 7.0MG/ML IN 10MM TRIS-HCL PH 7.4, 25MM NACL, WITH A 6-FOLD EXCESS OF NB-216 ADDED FROM A 50MM STOCK SOLUTION IN 90% DMSO-D6 (1.7% DMSO IN DROP). A SOLUTION CONTAINING 1.2M AMMONIUM SULFATE, 25% (V/V) GLYCEROL, 1.0MM NB-216 WAS USED AS CRYO-PROTECTANT., VAPOR DIFFUSION, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.97945 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 25, 2006 / Details: MIRRORS
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97945 Å / Relative weight: 1
ReflectionResolution: 2.12→70.55 Å / Num. all: 91081 / Num. obs: 91081 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.8 % / Biso Wilson estimate: 47.478 Å2 / Rmerge(I) obs: 0.048 / Rsym value: 0.048 / Net I/σ(I): 15.2
Reflection shellResolution: 2.12→2.19 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.377 / Mean I/σ(I) obs: 3.8 / Num. measured obs: 31995 / Num. unique all: 8430 / Num. unique obs: 8430 / Rsym value: 0.377 / % possible all: 99.9

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
CNSrefinement
PDB_EXTRACT3.005data extraction
XDSdata reduction
CNXphasing
CNX2005refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.12→70.55 Å / Rfactor Rfree error: 0.002 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.857 / Data cutoff high absF: 2265658 / 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
Rfree0.22 9103 10 %RANDOM
Rwork0.2 ---
all0.202 91081 --
obs0.202 91081 99.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 48.528 Å2 / ksol: 0.365 e/Å3
Displacement parametersBiso max: 118.36 Å2 / Biso mean: 48.348 Å2 / Biso min: 23.47 Å2
Baniso -1Baniso -2Baniso -3
1--1.11 Å20 Å20.15 Å2
2--3.97 Å20 Å2
3----2.85 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.28 Å0.25 Å
Luzzati d res low-5 Å
Luzzati sigma a0.25 Å0.21 Å
Refinement stepCycle: LAST / Resolution: 2.12→70.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8925 0 126 468 9519
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_dihedral_angle_d25.4
X-RAY DIFFRACTIONc_improper_angle_d0.61
X-RAY DIFFRACTIONc_mcbond_it1.561.5
X-RAY DIFFRACTIONc_mcangle_it2.62
X-RAY DIFFRACTIONc_scbond_it2.032
X-RAY DIFFRACTIONc_scangle_it3.072.5
LS refinement shellResolution: 2.12→2.25 Å / Rfactor Rfree error: 0.007 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.276 1493 9.9 %
Rwork0.252 13647 -
all-15140 -
obs-13647 100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4cis_peptide.paramnvp-bil216.top
X-RAY DIFFRACTION5nvp-bil216.param

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