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- PDB-4d89: Crystal Structure of Human Beta Secretase in Complex with NVP-BXD... -

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Basic information

Entry
Database: PDB / ID: 4d89
TitleCrystal Structure of Human Beta Secretase in Complex with NVP-BXD552, derived from a soaking experiment
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase inhibitor / Beta-Secretase / Memapsin2 / Bace1 / Aspartic Proteinase / Alzheimer's disease / Enzyme inhibitor complex / Structure-based drug design / Hydrolase / Hydrolase-Hydrolase inhibitor complex
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to manganese ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / recycling endosome / protein processing / response to lead ion / cellular response to amyloid-beta / synaptic vesicle / late endosome / peptidase activity / positive regulation of neuron apoptotic process / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / endosome membrane / endosome / membrane raft / endoplasmic reticulum lumen / Amyloid fiber formation / axon / neuronal cell body / dendrite / enzyme binding / cell surface / Golgi apparatus / 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-BXD / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.65 Å
AuthorsRondeau, J.M. / Bourgier, E.
Citation
Journal: J.Med.Chem. / Year: 2012
Title: Discovery of cyclic sulfone 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. / Rogel, O. / Rondeau, J.M. / Mobitz, H. / Machauer, R. / Jacobson, L. / Staufenbiel, M. / Desrayaud, S. / Neumann, U.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Structure-Based Design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors
Authors: Rueeger, H. / Rondeau, J.M. / McCarthy, C. / Moebitz, H. / Tintelnot-Blomley, M. / Neumann, U. / Desrayaud, S.
History
DepositionJan 10, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 21, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)45,3682
Polymers44,7771
Non-polymers5911
Water5,747319
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.771, 73.501, 103.992
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 / 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.: 1 / Fragment: Catalytic domain (unp residues 48-447)
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(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-BXD / (3S,4S,5R)-3-(4-amino-3-{[(2R)-3-ethoxy-1,1,1-trifluoropropan-2-yl]oxy}-5-fluorobenzyl)-5-[(3-tert-butylbenzyl)amino]tetrahydro-2H-thiopyran-4-ol 1,1-dioxide


Mass: 590.670 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H38F4N2O5S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 319 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.04 Å3/Da / Density % sol: 39.66 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: 15% PEG 1,500, in water, pH 5.2, vapor diffusion, hanging drop, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00161 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jan 31, 2008 / Details: mirrors
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00161 Å / Relative weight: 1
ReflectionResolution: 1.65→73.49 Å / Num. all: 44760 / Num. obs: 44760 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 5.4 % / Biso Wilson estimate: 25.644 Å2 / Rmerge(I) obs: 0.064 / Net I/σ(I): 15.79
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique allNum. unique obs% possible all
1.65-1.715.420.4583.94242984481448199.9
1.71-1.775.450.3754.88213353914391499.9
1.77-1.845.440.2946.22132439203920100
1.84-1.915.450.2268.05184543383338399.9
1.91-1.995.430.16210.791809633353335100
1.99-2.085.410.12713.221687931213121100
2.08-2.195.410.115.681726031883188100
2.19-2.325.380.08117.771627630263026100
2.32-2.465.40.07519.551398325912591100
2.46-2.655.370.06421.841463027252725100
2.65-2.885.350.05924.481273523822382100
2.88-3.185.290.05427.63116842208220899.8
3.18-3.65.260.04730.69104021979197999.7
3.6-4.255.210.0432.6790451735173599.7
4.25-5.455.10.03433.3573581443144399.9
5.45-8.634.960.03532.41494799899899.5
8.634.130.03430.41136833133187.6

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
CNSrefinement
PDB_EXTRACT3.1data extraction
XDSdata reduction
CNX2002phasing
CNX2002refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.65→42.45 Å / Rfactor Rfree error: 0.004 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8775 / Data cutoff high absF: 1625809 / 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
Rfree0.211 2238 5 %RANDOM
Rwork0.188 ---
all0.189 44759 --
obs0.189 44759 99.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 37.8046 Å2 / ksol: 0.3488 e/Å3
Displacement parametersBiso max: 58.1 Å2 / Biso mean: 22.6135 Å2 / Biso min: 9.77 Å2
Baniso -1Baniso -2Baniso -3
1-6.97 Å20 Å20 Å2
2---1.68 Å20 Å2
3----5.29 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.2 Å0.18 Å
Luzzati d res low-5 Å
Luzzati sigma a0.17 Å0.13 Å
Refinement stepCycle: LAST / Resolution: 1.65→42.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2953 0 40 319 3312
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_d25.4
X-RAY DIFFRACTIONc_improper_angle_d0.64
X-RAY DIFFRACTIONc_mcbond_it1.311.5
X-RAY DIFFRACTIONc_mcangle_it2.072
X-RAY DIFFRACTIONc_scbond_it2.192
X-RAY DIFFRACTIONc_scangle_it3.332.5
LS refinement shellResolution: 1.65→1.75 Å / Rfactor Rfree error: 0.014 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.271 367 5 %
Rwork0.237 6988 -
all-7355 -
obs-7355 99.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3CIS_PEPTIDE.PARAMNVP-BXD552.TOP
X-RAY DIFFRACTION4NVP-BXD552.PARAM

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