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- PDB-2of0: X-ray crystal structure of beta secretase complexed with compound 5 -

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Basic information

Entry
Database: PDB / ID: 2of0
TitleX-ray crystal structure of beta secretase complexed with compound 5
ComponentsBeta-secretase 1
KeywordsHYDROLASE / ALTERNATIVE SPLICING / ALZHEIMER'S DISEASE / ASPARTIC PROTEASE / ASPARTYL PROTEASE / BASE / BETA-SECRETASE / GLYCOPROTEIN / MEMAPSIN 2 / 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-CMZ / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsPatel, S.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Application of fragment screening by X-ray crystallography to beta-Secretase.
Authors: Murray, C.W. / Callaghan, O. / Chessari, G. / Cleasby, A. / Congreve, M. / Frederickson, M. / Hartshorn, M.J. / McMenamin, R. / Patel, S. / Wallis, N.
History
DepositionJan 2, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software
Revision 1.4Oct 20, 2021Group: Advisory / Database references / Derived calculations
Category: database_2 / pdbx_unobs_or_zero_occ_atoms ...database_2 / pdbx_unobs_or_zero_occ_atoms / 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 1.5Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.6Nov 6, 2024Group: Refinement description / Structure summary
Category: pdbx_entry_details / pdbx_modification_feature / software
Item: _software.name

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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)45,5666
Polymers44,8411
Non-polymers7245
Water3,225179
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)102.412, 102.412, 169.237
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
DetailsThe biological assembly is a monomer

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Components

#1: Protein Beta-secretase 1 / Beta-site APP cleaving enzyme 1 / Beta-site amyloid precursor protein cleaving enzyme 1 / Membrane- ...Beta-site APP cleaving enzyme 1 / Beta-site amyloid precursor protein cleaving enzyme 1 / Membrane-associated aspartic protease 2 / Memapsin-2 / Aspartyl protease 2 / Asp 2 / ASP2


Mass: 44841.395 Da / Num. of mol.: 1 / Fragment: protease domain / Mutation: R56K, R57K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE / Plasmid: pET / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-CMZ / (2S)-1-(2,5-dimethylphenoxy)-3-morpholin-4-ylpropan-2-ol / (S)-1-(2,5-dimethylphenoxy)-3-morpholinopropan-2-ol


Mass: 265.348 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H23NO3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 179 / 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: 2.97 Å3/Da / Density % sol: 58.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.6
Details: 20-22.5% (w/v) PEG 5000 monomethylether (MME), 200 mM sodium citrate (pH 6.6), 200 mM ammonium iodide, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Oct 24, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→38.2 Å / Num. all: 26905 / Num. obs: 24904

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0019crefinement
PDB_EXTRACT2data extraction
CrystalClear(MSC/RIGAKU)data collection
MOSFLMdata reduction
CCP4(SCALA)data scaling
CSearch(IN-HOUSE MR PROGRAMphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1W50

1w50


Resolution: 2.25→38.19 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.89 / SU B: 6.964 / SU ML: 0.174 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.272 / ESU R Free: 0.236 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28 1278 5.1 %RANDOM
Rwork0.22 ---
obs0.223 23631 97.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 36.407 Å2
Baniso -1Baniso -2Baniso -3
1--0.37 Å2-0.19 Å20 Å2
2---0.37 Å20 Å2
3---0.56 Å2
Refinement stepCycle: LAST / Resolution: 2.25→38.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2966 0 26 179 3171
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0223052
X-RAY DIFFRACTIONr_bond_other_d0.0020.022027
X-RAY DIFFRACTIONr_angle_refined_deg1.4071.9534150
X-RAY DIFFRACTIONr_angle_other_deg0.893.0024915
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9865375
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.12624.015137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.77415.092488
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.7391515
X-RAY DIFFRACTIONr_chiral_restr0.0790.2453
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023404
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02637
X-RAY DIFFRACTIONr_nbd_refined0.1930.2634
X-RAY DIFFRACTIONr_nbd_other0.2040.22118
X-RAY DIFFRACTIONr_nbtor_refined0.1850.21496
X-RAY DIFFRACTIONr_nbtor_other0.0890.21566
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1470.246
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1880.216
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2510.266
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1130.25
X-RAY DIFFRACTIONr_mcbond_it0.05551871
X-RAY DIFFRACTIONr_mcbond_other0.0215767
X-RAY DIFFRACTIONr_mcangle_it0.07663025
X-RAY DIFFRACTIONr_scbond_it0.07361181
X-RAY DIFFRACTIONr_scangle_it0.0897.51125
LS refinement shellResolution: 2.25→2.308 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.332 90 -
Rwork0.283 1420 -
obs-1510 82.15 %

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