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- PDB-7b1q: Crystal Structure of Human BACE-1 in Complex with Compound NB-360... -

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Basic information

Entry
Database: PDB / ID: 7b1q
TitleCrystal Structure of Human BACE-1 in Complex with Compound NB-360 (compound 54)
ComponentsBeta-secretase 1
KeywordsHYDROLASE / Beta-secretase / BACE1 / memaosin2 / aspartic acid proteinase / alzheimer's disease / enzyme-inhibitor complex / Structure-based drug design
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 / amyloid-beta metabolic process / prepulse inhibition ...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 / amyloid-beta metabolic process / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / protein serine/threonine kinase binding / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / hippocampal mossy fiber to CA3 synapse / 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 / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / lysosome / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / axon / 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. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily
Similarity search - Domain/homology
Chem-SLK / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.94 Å
AuthorsRondeau, J.M. / Wirth, E.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Synthesis of the Potent, Selective, and Efficacious beta-Secretase (BACE1) Inhibitor NB-360.
Authors: Rueeger, H. / Lueoend, R. / Machauer, R. / Veenstra, S.J. / Holzer, P. / Hurth, K. / Voegtle, M. / Frederiksen, M. / Rondeau, J.M. / Tintelnot-Blomley, M. / Jacobson, L.H. / Staufenbiel, M. ...Authors: Rueeger, H. / Lueoend, R. / Machauer, R. / Veenstra, S.J. / Holzer, P. / Hurth, K. / Voegtle, M. / Frederiksen, M. / Rondeau, J.M. / Tintelnot-Blomley, M. / Jacobson, L.H. / Staufenbiel, M. / Laue, G. / Neumann, U.
History
DepositionNov 25, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 28, 2021Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)45,2272
Polymers44,7771
Non-polymers4491
Water4,414245
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, The biological unit is a monomer. There is 1 biological unit in the asymmetric unit (chain A)
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.747, 74.158, 104.512
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Beta-secretase 1 / Aspartyl protease 2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP ...Aspartyl protease 2 / 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.: 1
Source method: isolated from a genetically manipulated source
Details: Refolded / Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Plasmid: pET24 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-SLK / ~{N}-[3-[(3~{R},6~{R})-5-azanyl-3,6-dimethyl-6-(trifluoromethyl)-2~{H}-1,4-oxazin-3-yl]-4-fluoranyl-phenyl]-5-cyano-3-methyl-pyridine-2-carboxamide


Mass: 449.401 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19F4N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 245 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.11 Å3/Da / Density % sol: 41.69 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 15% PEG 1,500 in water

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Feb 1, 2011 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.94→60.48 Å / Num. obs: 28735 / % possible obs: 99.9 % / Redundancy: 6.365 % / Biso Wilson estimate: 22 Å2 / Rmerge F obs: 0.083 / Rmerge(I) obs: 0.076 / Rrim(I) all: 0.083 / Χ2: 1.039 / Net I/σ(I): 13.89 / Num. measured all: 182894
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
1.94-2.026.7170.3480.3933.6521622321932190.426100
2.02-2.086.6670.2780.3234.6713921208820880.351100
2.08-2.156.5650.2250.2685.714306217921790.291100
2.15-2.226.1720.1980.2336.4811973194019400.255100
2.22-2.36.4880.1490.1868.1612211188218820.202100
2.3-2.396.7780.1220.1669.2412566185418540.18100
2.39-2.496.7390.1150.15310.3711887176817640.16699.8
2.49-2.616.6150.0940.1312.2411861179317930.142100
2.61-2.746.4150.0780.11214.2310257160415990.12299.7
2.74-2.96.0050.0660.09616.369482158515790.10599.6
2.9-3.096.3140.0520.08220.119389149014870.0999.8
3.09-3.316.3240.0420.06922.698506134713450.07599.9
3.31-3.66.0520.0350.05825.247867130213000.06499.8
3.6-3.975.7640.0320.05227.156698116611620.05899.7
3.97-4.55.3810.0290.04928.565747107410680.05499.4
4.5-5.316.0990.0230.04431.1457709479460.04899.9
5.31-6.85.9790.0230.04429.9646467807770.04899.6
6.8-10.965.5060.0220.03830.1230455555530.04299.6
10.96-60.485.70.0160.0332.6311402002000.033100

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
CNSrefinement
PDB_EXTRACT3.27data extraction
CNXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.94→60.48 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 1710379 / Data cutoff low absF: 0 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.218 1437 5 %RANDOM
Rwork0.189 ---
obs-28735 99.7 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 52.881 Å2 / ksol: 0.366 e/Å3
Displacement parametersBiso max: 68.06 Å2 / Biso mean: 32.2 Å2 / Biso min: 14.48 Å2
Baniso -1Baniso -2Baniso -3
1-5.17 Å20 Å20 Å2
2--5.3 Å20 Å2
3----10.46 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.25 Å0.21 Å
Luzzati d res low-5 Å
Luzzati sigma a0.14 Å0.15 Å
Refinement stepCycle: final / Resolution: 1.94→60.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2984 0 32 245 3261
Biso mean--28.05 39.52 -
Num. residues----379
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_dihedral_angle_d22.5
X-RAY DIFFRACTIONc_improper_angle_d0.63
X-RAY DIFFRACTIONc_mcbond_it1.461.5
X-RAY DIFFRACTIONc_mcangle_it2.332
X-RAY DIFFRACTIONc_scbond_it2.212
X-RAY DIFFRACTIONc_scangle_it3.332.5
LS refinement shellResolution: 1.94→2.06 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.242 236 5 %
Rwork0.223 4480 -
all-4716 -
obs--100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3nvp-chs360.paramnvp-chs360.top
X-RAY DIFFRACTION4cis_peptide.param

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