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- PDB-3udh: Crystal Structure of BACE with Compound 1 -

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Basic information

Entry
Database: PDB / ID: 3udh
TitleCrystal Structure of BACE with Compound 1
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
(3S)-spiro[indole-3,3'-pyrrolidin]-2(1H)-one / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / RIGID BODY REFINEMENT / Resolution: 1.7 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 1.2Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Oct 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 / pdbx_struct_special_symmetry / 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)45,7839
Polymers45,1571
Non-polymers6268
Water5,747319
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.803, 103.750, 99.593
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-855-

HOH

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Components

#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
#2: Chemical ChemComp-091 / (3S)-spiro[indole-3,3'-pyrrolidin]-2(1H)-one


Mass: 188.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H12N2O
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-ZN / ZINC ION


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


Mass: 18.015 Da / Num. of mol.: 319 / 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: 42.51 %
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: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Apr 10, 2008
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→46.03 Å / Num. obs: 41969 / % possible obs: 98.7 % / Redundancy: 4.73 % / Rmerge(I) obs: 0.043 / Net I/σ(I): 13.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.7-1.773.810.4172.8190.5
1.77-1.844.820.3533.11100
1.84-1.924.810.25741100
1.92-2.024.820.175.71100
2.02-2.154.820.1227.71100
2.15-2.314.80.0919.91100
2.31-2.554.870.07311.9199.9
2.55-2.924.870.05317199.8
2.92-3.674.890.03524.5199.5
3.67-46.0294.740.02441.3196.9

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Processing

Software
NameVersionClassificationNB
d*TREK9.6Ldata scaling
d*TREK9.6Ldata reduction
REFMAC5.2.0019refinement
PDB_EXTRACT3.1data extraction
MAR345data collection
autoBUSTERphasing
RefinementMethod to determine structure: RIGID BODY REFINEMENT / Resolution: 1.7→46.03 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.943 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 2.647 / SU ML: 0.086 / Cross valid method: THROUGHOUT / ESU R: 0.125 / ESU R Free: 0.124 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24137 2138 5.1 %RANDOM
Rwork0.19594 ---
obs0.19826 39787 98.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.283 Å2
Baniso -1Baniso -2Baniso -3
1--0.13 Å20 Å20 Å2
2---0.19 Å20 Å2
3---0.32 Å2
Refinement stepCycle: LAST / Resolution: 1.7→46.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3106 0 39 319 3464
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0223223
X-RAY DIFFRACTIONr_bond_other_d00.022170
X-RAY DIFFRACTIONr_angle_refined_deg1.2161.9494373
X-RAY DIFFRACTIONr_angle_other_deg0.75835263
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7795392
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.10223.826149
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.19515507
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7581518
X-RAY DIFFRACTIONr_chiral_restr0.0850.2473
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0213600
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02681
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2990.2265
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0190.21
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2380.218
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2420.252
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2010.217
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.5011.51955
X-RAY DIFFRACTIONr_mcbond_other0.461.5800
X-RAY DIFFRACTIONr_mcangle_it2.53523165
X-RAY DIFFRACTIONr_scbond_it3.51931268
X-RAY DIFFRACTIONr_scangle_it5.6064.51208
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.749 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.463 116 -
Rwork0.432 2576 -
obs--86.98 %

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