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- PDB-4d88: Crystal Structure of Human Beta Secretase in Complex with NVP-BXQ490 -

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Basic information

Entry
Database: PDB / ID: 4d88
TitleCrystal Structure of Human Beta Secretase in Complex with NVP-BXQ490
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 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 / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / 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 / cellular response to copper ion / protein serine/threonine kinase binding / presynaptic modulation of chemical synaptic transmission / multivesicular body / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / response to lead ion / protein processing / recycling endosome / 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 / endosome membrane / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / 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-BXQ / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.7 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)45,3242
Polymers44,7771
Non-polymers5471
Water9,872548
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.876, 74.897, 104.579
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: 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-BXQ / (3S,4S,5R)-3-{4-amino-3-fluoro-5-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]benzyl}-5-[(3-tert-butylbenzyl)amino]tetrahydro-2H-thiopyran-4-ol 1,1-dioxide


Mass: 546.618 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H34F4N2O4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 548 / 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: 2.14 Å3/Da / Density % sol: 42.45 %
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: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Feb 12, 2008 / Details: mirrors
RadiationMonochromator: MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.7→74.89 Å / Num. all: 42415 / Num. obs: 42415 / % possible obs: 98.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 7 % / Biso Wilson estimate: 23.487 Å2 / Rmerge(I) obs: 0.057 / Net I/σ(I): 22.27
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
1.7-1.776.530.3076.18281174306430689.6
1.77-1.836.940.2687.31246903558355898.8
1.83-1.886.930.2338.36181502620262099.3
1.88-1.956.960.18210.55226303252325299.6
1.95-2.026.980.14213.05196722818281899.6
2.02-2.16.990.11715.69193562771277199.7
2.1-2.197.030.09818.37188522683268399.9
2.19-2.297.040.08121.48176042500250099.9
2.29-2.417.070.07323.391767225002500100
2.41-2.547.090.06626.121551021882188100
2.54-2.717.130.05629.311636722972297100
2.71-2.917.130.04932.871463520532053100
2.91-3.167.160.04137.721350618871887100
3.16-3.497.110.03840.891256217681768100
3.49-3.957.130.03245.841111415591559100
3.95-4.677.040.02951.8989914071407100
4.67-5.987.010.02950.06802911451145100
5.98-9.576.770.02851.55554820820100
9.575.970.02652.61169028328397.3

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
CNSrefinement
PDB_EXTRACT3.1data extraction
MAR345dtbdata collection
XDSdata reduction
CNX2002phasing
CNX2002refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.7→52.29 Å / Rfactor Rfree error: 0.005 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.895 / Data cutoff high absF: 1723551 / 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
Rfree0.214 2121 5 %RANDOM
Rwork0.176 ---
all0.178 42415 --
obs0.178 42415 98.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 47.5365 Å2 / ksol: 0.3469 e/Å3
Displacement parametersBiso max: 57.3 Å2 / Biso mean: 20.1176 Å2 / Biso min: 6.84 Å2
Baniso -1Baniso -2Baniso -3
1-0.08 Å20 Å20 Å2
2--1.99 Å20 Å2
3----2.07 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.2 Å0.17 Å
Luzzati d res low-5 Å
Luzzati sigma a0.14 Å0.12 Å
Refinement stepCycle: LAST / Resolution: 1.7→52.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2953 0 37 548 3538
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_d23.7
X-RAY DIFFRACTIONc_improper_angle_d0.65
X-RAY DIFFRACTIONc_mcbond_it1.281.5
X-RAY DIFFRACTIONc_mcangle_it1.992
X-RAY DIFFRACTIONc_scbond_it2.082
X-RAY DIFFRACTIONc_scangle_it3.12.5
LS refinement shellResolution: 1.7→1.81 Å / Rfactor Rfree error: 0.013 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.236 327 5 %
Rwork0.209 6218 -
all-6545 -
obs-6545 92.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3cis_peptide.paramnvp-bxq490_S.top
X-RAY DIFFRACTION4nvp-bxq490_S.param

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