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- PDB-3exo: Crystal structure of BACE1 bound to inhibitor -

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Basic information

Entry
Database: PDB / ID: 3exo
TitleCrystal structure of BACE1 bound to inhibitor
ComponentsBeta-secretase 1
KeywordsHYDROLASE / beta secretase / bace 1 / aspartyl protease / Glycoprotein / Membrane / Protease / Transmembrane / Zymogen
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-5MS / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.1 Å
AuthorsAllison, T.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement.
Authors: Steele, T.G. / Hills, I.D. / Nomland, A.A. / de Leon, P. / Allison, T. / McGaughey, G. / Colussi, D. / Tugusheva, K. / Haugabook, S.J. / Espeseth, A.S. / Zuck, P. / Graham, S.L. / Stachel, S.J.
History
DepositionOct 16, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 3, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / 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
Revision 1.4Dec 27, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.5Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)46,7296
Polymers45,9951
Non-polymers7355
Water7,512417
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.433, 127.923, 76.671
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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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: 45994.633 Da / Num. of mol.: 1 / Fragment: UNP residues 43-454 / Mutation: K75A, E77A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#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-5MS / N-{2-methyl-5-[(6-phenylpyrimidin-4-yl)amino]phenyl}methanesulfonamide


Mass: 354.426 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18N4O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 417 / 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: 2.78 Å3/Da / Density % sol: 55.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 1.5M Lithium Sulfate, 0.1M HEPES pH 7.5; crystals were soaked in 1.5M Lithium Sulfate, 0.1M Na Citrate, pH 5.0, 0.5mM inhibitor, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Nov 10, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 30130 / % possible obs: 98.9 % / Redundancy: 4.9 % / Rmerge(I) obs: 0.105 / Χ2: 1.088 / Net I/σ(I): 16.347
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.1-2.1850.47130131.051199.9
2.18-2.264.50.33329761.883199.1
2.26-2.374.90.49529831.27199.7
2.37-2.4950.24830061.033199.5
2.49-2.6550.19630080.973199.6
2.65-2.854.90.15130021.126199.2
2.85-3.1450.08730000.855199.2
3.14-3.5950.07230110.956198.6
3.59-4.524.90.05630241.054198.2
4.52-504.90.03231070.786196.8

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.006data extraction
StructureStudiodata collection
MOLREPphasing
RefinementResolution: 2.1→32.88 Å / Cor.coef. Fo:Fc: 0.908 / Cor.coef. Fo:Fc free: 0.876 / WRfactor Rfree: 0.253 / WRfactor Rwork: 0.196 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.742 / SU B: 6.518 / SU ML: 0.164 / SU R Cruickshank DPI: 0.247 / SU Rfree: 0.226 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.247 / ESU R Free: 0.226 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.295 1497 5.2 %RANDOM
Rwork0.229 ---
obs0.232 28851 95.06 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 124.57 Å2 / Biso mean: 19.184 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å20 Å2
2--0.08 Å20 Å2
3----0.06 Å2
Refinement stepCycle: LAST / Resolution: 2.1→32.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2926 0 46 417 3389
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0223049
X-RAY DIFFRACTIONr_angle_refined_deg1.4821.9614147
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5845370
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.3523.723137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.98115474
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.381517
X-RAY DIFFRACTIONr_chiral_restr0.0970.2444
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022338
X-RAY DIFFRACTIONr_nbd_refined0.1990.21304
X-RAY DIFFRACTIONr_nbtor_refined0.3090.22013
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1580.2297
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1740.256
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2040.225
X-RAY DIFFRACTIONr_mcbond_it0.7811.51908
X-RAY DIFFRACTIONr_mcangle_it1.27522997
X-RAY DIFFRACTIONr_scbond_it1.93531327
X-RAY DIFFRACTIONr_scangle_it2.954.51150
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.483 122 -
Rwork0.354 2060 -
all-2182 -
obs--98.47 %

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