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- PDB-3vg1: Crystal Structure of Human Beta Secretase in Complex with NVP-BUR... -

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Basic information

Entry
Database: PDB / ID: 3vg1
TitleCrystal Structure of Human Beta Secretase in Complex with NVP-BUR436, 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 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / multivesicular body / hippocampal mossy fiber to CA3 synapse / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / 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. / 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-0GT / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.77 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. / Mobitz, 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)45,2822
Polymers44,7771
Non-polymers5051
Water6,503361
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.702, 72.239, 104.585
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 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-0GT / (3R,4S,5S)-3-[(3-tert-butylbenzyl)amino]-5-{[3-(2,2-difluoroethyl)-1H-indol-5-yl]methyl}tetrahydro-2H-thiopyran-4-ol 1,1-dioxide


Mass: 504.632 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H34F2N2O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 361 / 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: 2.05 Å3/Da / Density % sol: 40.13 %
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: 1.77→72.14 Å / Num. all: 36626 / Num. obs: 36626 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 5 % / Biso Wilson estimate: 26.578 Å2 / Rmerge(I) obs: 0.068 / Net I/σ(I): 14.42
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
1.77-1.823.920.4333.46113352892289299.7
1.82-1.883.940.3723.99120873070307099.7
1.88-1.954.830.2775.83151523137313799.7
1.95-2.025.350.2117.81145122715271599.6
2.02-2.15.340.1659.65142552667266799.9
2.1-2.185.330.12811.73123452314231499.8
2.18-2.295.340.10913.51142302664266499.9
2.29-2.45.330.09614.75117702208220899.9
2.4-2.545.350.08616.171233723052305100
2.54-2.75.320.07717.441112820902090100
2.7-2.95.30.07119.191061220042004100
2.9-3.165.270.06420.42998918951895100
3.16-3.495.250.05323.4289181699169999.9
3.49-3.955.240.04926.7178241493149399.6
3.95-4.665.230.03930.9769381326132699.3
4.66-5.975.140.03534.0557521119111999.9
5.97-9.414.970.03534.74383877377399.6
9.414.190.03233.29106825525586.4

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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: 1.77→59.44 Å / Rfactor Rfree error: 0.005 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8811 / Data cutoff high absF: 1687942 / 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
Rfree0.217 1832 5 %RANDOM
Rwork0.187 ---
all0.188 36618 --
obs0.188 36618 99.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 45.2271 Å2 / ksol: 0.3544 e/Å3
Displacement parametersBiso max: 68.57 Å2 / Biso mean: 25.8416 Å2 / Biso min: 8.77 Å2
Baniso -1Baniso -2Baniso -3
1-7.79 Å20 Å20 Å2
2---1.66 Å20 Å2
3----6.13 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.22 Å0.19 Å
Luzzati d res low-5 Å
Luzzati sigma a0.18 Å0.13 Å
Refinement stepCycle: LAST / Resolution: 1.77→59.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2960 0 35 361 3356
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_dihedral_angle_d27.6
X-RAY DIFFRACTIONc_improper_angle_d0.62
X-RAY DIFFRACTIONc_mcbond_it1.521.5
X-RAY DIFFRACTIONc_mcangle_it2.42
X-RAY DIFFRACTIONc_scbond_it2.192
X-RAY DIFFRACTIONc_scangle_it3.372.5
LS refinement shellResolution: 1.77→1.88 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.275 299 5 %
Rwork0.236 5695 -
all-5994 -
obs-5994 99.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3cis_peptide.paramnvp-bur436.top
X-RAY DIFFRACTION4nvp-bur436.param

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