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- PDB-4lxa: Crystal Structure of Human Beta Secretase in Complex with Compound 11a -

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Basic information

Entry
Database: PDB / ID: 4lxa
TitleCrystal Structure of Human Beta Secretase in Complex with Compound 11a
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Structure-based drug design / Aspartyl protease / Membrane / 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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion ...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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / 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 / positive regulation of neuron apoptotic process / cellular response to amyloid-beta / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / 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. / 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-1YS / PHOSPHATE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.95 Å
AuthorsRondeau, J.M. / Bourgier, E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of cyclic sulfoxide 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. / Machauer, R. / Veenstra, S.J. / Jacobson, L.H. / Staufenbiel, M. / Desrayaud, S. / Rondeau, J.M. / Mobitz, H. / Neumann, U.
History
DepositionJul 29, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2013Group: Other
Revision 1.2Nov 20, 2013Group: Database references
Revision 1.3Nov 15, 2017Group: Refinement description / Category: software
Revision 1.4Oct 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

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)136,2738
Polymers134,3323
Non-polymers1,9415
Water9,242513
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3622
Polymers44,7771
Non-polymers5851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,4543
Polymers44,7771
Non-polymers6772
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,4573
Polymers44,7771
Non-polymers6802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.931, 103.070, 100.227
Angle α, β, γ (deg.)90.00, 104.33, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 3 / Fragment: Catalytic domain, UNP residues 48-447
Source method: isolated from a genetically manipulated source
Details: Refolded / 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-1YS / (1R,3S,4S,5R)-3-{4-amino-3-fluoro-5-[(1,1,1,3,3,3-hexafluoropropan-2-yl)oxy]benzyl}-5-[(3-tert-butylbenzyl)amino]tetrahydro-2H-thiopyran-4-ol 1-oxide


Mass: 584.590 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C26H31F7N2O3S
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 513 / 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: 3.05 Å3/Da / Density % sol: 59.7 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 1.0M ammonium phosphate, 0.1M sodium citrate, pH 5.0, 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 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Mar 19, 2008 / Details: mirrors
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. all: 116573 / Num. obs: 116573 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.3 % / Biso Wilson estimate: 28.8 Å2 / Rmerge(I) obs: 0.086 / Χ2: 0.997 / Net I/σ(I): 8.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.95-2.026.30.435116220.3061100
2.02-2.16.30.309116340.3221100
2.1-2.26.40.224116010.3541100
2.2-2.316.40.164116680.4111100
2.31-2.466.40.136116400.4831100
2.46-2.656.40.108116660.6391100
2.65-2.916.40.093116640.921100
2.91-3.336.40.086116821.5641100
3.33-4.26.30.079117182.466199.9
4.2-506.10.07116782.569198.3

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
CNXphasing
CNXrefinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.95→37.65 Å / Rfactor Rfree error: 0.003 / Occupancy max: 1 / Occupancy min: 1 / Data cutoff high absF: 19351216 / 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
Rfree0.222 5880 5 %RANDOM
Rwork0.199 ---
all0.2 116548 --
obs0.2 116548 99.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 49.3849 Å2 / ksol: 0.3759 e/Å3
Displacement parametersBiso max: 110.51 Å2 / Biso mean: 42.5006 Å2 / Biso min: 21.59 Å2
Baniso -1Baniso -2Baniso -3
1-0.86 Å20 Å21.21 Å2
2--2.92 Å20 Å2
3----3.79 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.26 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.18 Å0.16 Å
Refinement stepCycle: LAST / Resolution: 1.95→37.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8925 0 128 513 9566
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
X-RAY DIFFRACTIONc_improper_angle_d0.66
X-RAY DIFFRACTIONc_mcbond_it1.531.5
X-RAY DIFFRACTIONc_mcangle_it2.482
X-RAY DIFFRACTIONc_scbond_it1.992
X-RAY DIFFRACTIONc_scangle_it32.5
LS refinement shellResolution: 1.95→2.07 Å / Rfactor Rfree error: 0.009 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.271 942 5 %
Rwork0.24 17802 -
all-18744 -
obs-18744 96.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3CIS_PEPTIDE.PARAMNVP-BXT856.TOP
X-RAY DIFFRACTION4NVP-BXT856_GLYCEROL.PARAMION.TOP
X-RAY DIFFRACTION5ION.PARAMGLYCEROL.TOP

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