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- PDB-3udj: Crystal Structure of BACE with Compound 5 -

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Basic information

Entry
Database: PDB / ID: 3udj
TitleCrystal Structure of BACE with Compound 5
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / 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-092 / DI(HYDROXYETHYL)ETHER / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / RIGID BODY REFINEMENT / Resolution: 1.8 Å
AuthorsEfremov, I.V. / Vajdos, F.F. / Borzilleri, K. / Capetta, S. / Dorff, P. / Dutra, J. / Mansour, M. / Oborski, C. / O'Connell, T. / O'Sullivan, T.J. ...Efremov, I.V. / Vajdos, F.F. / Borzilleri, K. / Capetta, S. / Dorff, P. / Dutra, J. / Mansour, M. / Oborski, C. / O'Connell, T. / O'Sullivan, T.J. / Pandit, J. / Wang, H. / Withka, J.
Citation
Journal: J.Med.Chem. / Year: 2012
Title: Discovery and optimization of a novel spiropyrrolidine inhibitor of {beta}-secretase (BACE1) through fragment-based drug design.
Authors: Efremov, I.V. / Vajdos, F.F. / Borzilleri, K.A. / Capetta, S. / Chen, H. / Dorff, P.H. / Dutra, J.K. / Goldstein, S.W. / Mansour, M. / McColl, A. / Noell, S. / Oborski, C.E. / O'Connell, T.N. ...Authors: Efremov, I.V. / Vajdos, F.F. / Borzilleri, K.A. / Capetta, S. / Chen, H. / Dorff, P.H. / Dutra, J.K. / Goldstein, S.W. / Mansour, M. / McColl, A. / Noell, S. / Oborski, C.E. / O'Connell, T.N. / O'Sullivan, T.J. / Pandit, J. / Wang, H. / Wei, B. / Withka, J.M.
#1: Journal: Protein Pept.Lett. / Year: 2008
Title: High yield expression of human BACE constructs in Escherichia coli for refolding, purification, and high resolution diffracting crystal forms.
Authors: Tomasselli, A.G. / Paddock, D.J. / Emmons, T.L. / Mildner, A.M. / Leone, J.W. / Lull, J.M. / Cialdella, J.I. / Prince, D.B. / Fischer, H.D. / Heinrikson, R.L. / Benson, T.E.
History
DepositionOct 28, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 18, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2013Group: Database references
Revision 1.2Oct 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_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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,6996
Polymers45,1571
Non-polymers5425
Water4,306239
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.113, 104.016, 100.847
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Beta-secretase 1 / BACE / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / ...BACE / 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: 45156.730 Da / Num. of mol.: 1 / Fragment: UNP residues 58-453
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2

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Non-polymers , 5 types, 244 molecules

#2: Chemical ChemComp-092 / methyl (3S,5'R)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate


Mass: 246.262 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H14N2O3
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 239 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.18 Å3/Da / Density % sol: 43.6 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: protein in sodium borate, pH 8.5, reservoir: 30% PEG200, 0.1 M sodium acetate, pH 5.2-5.4, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS / Detector: IMAGE PLATE / Date: Aug 22, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→38.65 Å / Num. obs: 36322 / % possible obs: 99.4 % / Redundancy: 4.62 % / Rmerge(I) obs: 0.05 / Χ2: 0.96 / Net I/σ(I): 12.5 / Scaling rejects: 1270
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2% possible all
1.8-1.863.480.35631199134351.2695
1.86-1.944.630.3253.41677036091.24100
1.94-2.034.70.2454.31697035921.15100
2.03-2.134.690.1895.51717836341.0999.9
2.13-2.274.750.1387.31725736030.95100
2.27-2.444.790.1118.81752836370.9299.9
2.44-2.694.790.08211.51758736500.82100
2.69-3.084.840.057161778936630.78100
3.08-3.884.860.03824.21799136890.73100
3.88-38.654.660.029361819038100.899.4

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Processing

Software
NameVersionClassificationNB
d*TREK9.6Ldata scaling
d*TREK9.6Ldata reduction
REFMAC5.4.0069refinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: RIGID BODY REFINEMENT / Resolution: 1.8→31.48 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.927 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 3.009 / SU ML: 0.096 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.153 / ESU R Free: 0.143 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2487 1888 5.2 %RANDOM
Rwork0.2069 ---
obs0.209 36310 98.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 71.38 Å2 / Biso mean: 30.4301 Å2 / Biso min: 14.67 Å2
Baniso -1Baniso -2Baniso -3
1--0.79 Å20 Å20 Å2
2---0.92 Å20 Å2
3---1.71 Å2
Refinement stepCycle: LAST / Resolution: 1.8→31.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3102 0 34 239 3375
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0223217
X-RAY DIFFRACTIONr_bond_other_d00.022160
X-RAY DIFFRACTIONr_angle_refined_deg1.1731.954371
X-RAY DIFFRACTIONr_angle_other_deg0.8013.0025234
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.8255392
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.88523.784148
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.45615505
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2491518
X-RAY DIFFRACTIONr_chiral_restr0.0770.2473
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.0213600
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02681
X-RAY DIFFRACTIONr_mcbond_it1.4131.51955
X-RAY DIFFRACTIONr_mcbond_other0.4361.5800
X-RAY DIFFRACTIONr_mcangle_it2.2923164
X-RAY DIFFRACTIONr_scbond_it3.33931262
X-RAY DIFFRACTIONr_scangle_it5.0354.51207
LS refinement shellResolution: 1.8→1.849 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.391 108 -
Rwork0.295 2164 -
all-2272 -
obs--84.71 %

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