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- PDB-4d85: Crystal Structure of Human Beta Secretase in Complex with NVP-BVI151 -

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Basic information

Entry
Database: PDB / ID: 4d85
TitleCrystal Structure of Human Beta Secretase in Complex with NVP-BVI151
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-0GU / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.65 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 1.1Oct 16, 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)46,1273
Polymers45,4351
Non-polymers6922
Water1,72996
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.656, 102.656, 170.902
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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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: 45434.957 Da / Num. of mol.: 1 / Fragment: Catalytic domain (unp residues 48-453)
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-0GU / (3R,4S,5S)-3-[(3-tert-butylbenzyl)amino]-5-[(4,4,7'-trifluoro-1',2'-dihydrospiro[cyclohexane-1,3'-indol]-5'-yl)methyl]tetrahydro-2H-thiopyran-4-ol 1,1-dioxide


Mass: 564.702 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H39F3N2O3S
#3: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 96 / 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: 2.86 Å3/Da / Density % sol: 57 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2M sodium citrate pH 6.5, 0.2M sodium iodide, 25% PEG MME 5,000, vapor diffusion, hanging drop, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00146 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 22, 2007 / Details: mirrors
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00146 Å / Relative weight: 1
ReflectionResolution: 2.65→100 Å / Num. all: 15949 / Num. obs: 15949 / % possible obs: 98.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.5 % / Rmerge(I) obs: 0.099 / Χ2: 0.969 / Net I/σ(I): 6.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.65-2.743.50.4715450.786198.5
2.74-2.853.50.38115530.854199.1
2.85-2.983.50.29215630.919199.2
2.98-3.143.50.22115641.021199.4
3.14-3.343.50.17115841.081199.5
3.34-3.63.50.12515811.162199.2
3.6-3.963.50.08916091.213199.2
3.96-4.533.40.06516051.074199
4.53-5.713.40.04716280.734198
5.71-1003.20.04717170.836195.3

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3.1data extraction
CNX2002phasing
CNX2002refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.65→35.05 Å / Rfactor Rfree error: 0.009 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8416 / Data cutoff high absF: 36578136 / 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
Rfree0.247 779 4.9 %RANDOM
Rwork0.207 ---
all0.209 15939 --
obs0.209 15939 98.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 47.0758 Å2 / ksol: 0.3721 e/Å3
Displacement parametersBiso max: 89.73 Å2 / Biso mean: 38.9528 Å2 / Biso min: 11.45 Å2
Baniso -1Baniso -2Baniso -3
1--8.1 Å24.43 Å20 Å2
2---8.1 Å20 Å2
3---16.2 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.37 Å0.29 Å
Luzzati d res low-5 Å
Luzzati sigma a0.43 Å0.34 Å
Refinement stepCycle: LAST / Resolution: 2.65→35.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2941 0 40 96 3077
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_dihedral_angle_d28.4
X-RAY DIFFRACTIONc_improper_angle_d0.68
X-RAY DIFFRACTIONc_mcbond_it1.361.5
X-RAY DIFFRACTIONc_mcangle_it2.332
X-RAY DIFFRACTIONc_scbond_it1.982
X-RAY DIFFRACTIONc_scangle_it3.082.5
LS refinement shellResolution: 2.65→2.82 Å / Rfactor Rfree error: 0.035 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.373 115 4.5 %
Rwork0.287 2457 -
all-2572 -
obs-2572 98.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3ION.PARAMNVP-BVI151.TOP
X-RAY DIFFRACTION4NVP-BVI151.PARAM

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