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- PDB-3l5d: Structure of BACE Bound to SCH723873 -

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Basic information

Entry
Database: PDB / ID: 3l5d
TitleStructure of BACE Bound to SCH723873
ComponentsBeta-secretase 1
KeywordsHYDROLASE / BACE1 / Alzheimers / Alternative splicing / Aspartyl protease / Disulfide bond / Endoplasmic reticulum / Endosome / Glycoprotein / Golgi apparatus / Membrane / Polymorphism / Protease / Transmembrane / Zymogen
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-BDV / D(-)-TARTARIC ACID / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsStrickland, C. / Zhu, Z.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Discovery of Cyclic Acylguanidines as Highly Potent and Selective beta-Site Amyloid Cleaving Enzyme (BACE) Inhibitors: Part I-Inhibitor Design and Validation
Authors: Zhu, Z. / Sun, Z.Y. / Ye, Y. / Voigt, J. / Strickland, C. / Smith, E.M. / Cumming, J. / Wang, L. / Wong, J. / Wang, Y.S. / Wyss, D.F. / Chen, X. / Kuvelkar, R. / Kennedy, M.E. / Favreau, L. ...Authors: Zhu, Z. / Sun, Z.Y. / Ye, Y. / Voigt, J. / Strickland, C. / Smith, E.M. / Cumming, J. / Wang, L. / Wong, J. / Wang, Y.S. / Wyss, D.F. / Chen, X. / Kuvelkar, R. / Kennedy, M.E. / Favreau, L. / Parker, E. / McKittrick, B.A. / Stamford, A. / Czarniecki, M. / Greenlee, W. / Hunter, J.C.
History
DepositionDec 21, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 16, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Oct 30, 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,7257
Polymers92,5002
Non-polymers1,2255
Water16,592921
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,7883
Polymers46,2501
Non-polymers5382
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,9384
Polymers46,2501
Non-polymers6883
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.233, 89.222, 130.599
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 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Membrane- ...Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Membrane-associated aspartic protease 2 / Memapsin-2 / Aspartyl protease 2 / Asp 2 / ASP2


Mass: 46249.926 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-TAR / D(-)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H6O6
#3: Chemical ChemComp-BDV / 1-butyl-3-(4-{[(2Z,4R)-2-imino-4-methyl-4-(2-methylpropyl)-5-oxoimidazolidin-1-yl]methyl}benzyl)urea


Mass: 387.519 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H33N5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 921 / 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: 2.72 Å3/Da / Density % sol: 54.71 %
Crystal growTemperature: 277 K / Method: hanging drop / Details: Hanging Drop, temperature 277K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 22, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→35.63 Å / Num. obs: 110768 / % possible obs: 99.8 % / Rmerge(I) obs: 0.074 / Χ2: 0.99 / Net I/σ(I): 8.2
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2% possible all
1.7-1.730.57254730.85299.8
1.73-1.760.47554520.85299.9
1.76-1.790.41854880.84199.8
1.79-1.830.32954750.86499.9
1.83-1.870.29355050.87999.9
1.87-1.910.27754821.11499.7
1.91-1.960.2154731.07599.7
1.96-2.020.15854780.99499.9
2.02-2.070.15655271.16999.7
2.07-2.140.11855241.01999.9
2.14-2.220.10254940.98199.9
2.22-2.310.10855001.10999.7
2.31-2.410.08355370.98299.9
2.41-2.540.07655650.977100
2.54-2.70.07155511.03799.9
2.7-2.910.05655381.003100
2.91-3.20.04656121.01399.9
3.2-3.660.0456021.02899.7
3.66-4.610.03656611.01499.7
4.61-500.03558311.01198.6

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3.005data extraction
ADSCQuantumdata collection
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→35.63 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.842 / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.223 5095 5 %
Rwork0.199 --
obs-101819 99.8 %
Displacement parametersBiso max: 73.03 Å2 / Biso min: 5.15 Å2
Refinement stepCycle: LAST / Resolution: 1.75→35.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6080 0 86 921 7087
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_d1.784
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1parasch723873.protopsch723873.pro
X-RAY DIFFRACTION2paratartrate.protoptartrate.pro
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.paramMSI_CNX_TOPPAR:water.top
X-RAY DIFFRACTION4MSI_CNX_TOPPAR:ion.paramMSI_CNX_TOPPAR:ion.top
X-RAY DIFFRACTION5MSI_CNX_TOPPAR:protein_rep.paramMSI_CNX_TOPPAR:protein.top

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