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- PDB-2ohp: X-ray crystal structure of beta secretase complexed with compound 3 -

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Basic information

Entry
Database: PDB / ID: 2ohp
TitleX-ray crystal structure of beta secretase complexed with compound 3
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-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
6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMINE / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsPatel, S.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of beta-secretase.
Authors: Congreve, M. / Aharony, D. / Albert, J. / Callaghan, O. / Campbell, J. / Carr, R.A. / Chessari, G. / Cowan, S. / Edwards, P.D. / Frederickson, M. / McMenamin, R. / Murray, C.W. / Patel, S. / Wallis, N.
History
DepositionJan 10, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 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: Refinement description / Category: software
Revision 1.4Oct 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 1.5Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.6Oct 30, 2024Group: Refinement description / Structure summary
Category: pdbx_entry_details / pdbx_modification_feature / software
Item: _software.name
Remark 600 HETEROGEN THERE IS AN EXTRA ATOM H20 IN MOLECULE 6IP. AUTHOR STATES THAT THE MOLECULE 6IP IS ... HETEROGEN THERE IS AN EXTRA ATOM H20 IN MOLECULE 6IP. AUTHOR STATES THAT THE MOLECULE 6IP IS PROTONATED (CHARGED) UNDER THE PH CONDITIONS OF THE EXPERIMENT, AND THIS PROTONATION STATE IS CRITICAL TO THE BINDING MODE OBSERVED.

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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)45,4115
Polymers44,8411
Non-polymers5694
Water2,216123
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)102.541, 102.541, 169.062
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-493-

HOH

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.: 2 / 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-6IP / 6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMINE


Mass: 237.300 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H15N3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 123 / 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: 2.86 Å3/Da / Density % sol: 56.99 %
Crystal growTemperature: 293 K / 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, pH 6.60

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.934
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Apr 30, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 2.25→47.58 Å / Num. obs: 25567 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.091

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0019grefinement
PDB_EXTRACT2data extraction
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→47.58 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.898 / SU B: 7.141 / SU ML: 0.179 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.272 / ESU R Free: 0.231 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.281 1304 5.1 %RANDOM
Rwork0.232 ---
obs0.234 25567 99.7 %-
all-25567 --
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: 36.79 Å2
Baniso -1Baniso -2Baniso -3
1--0.21 Å2-0.1 Å20 Å2
2---0.21 Å20 Å2
3---0.31 Å2
Refinement stepCycle: LAST / Resolution: 2.25→47.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2966 0 40 123 3129
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0223067
X-RAY DIFFRACTIONr_bond_other_d0.0020.022055
X-RAY DIFFRACTIONr_angle_refined_deg1.4211.9424170
X-RAY DIFFRACTIONr_angle_other_deg0.9012.9934977
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2125375
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.62323.857140
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.01415.031485
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2851517
X-RAY DIFFRACTIONr_chiral_restr0.080.2452
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023433
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02657
X-RAY DIFFRACTIONr_nbd_refined0.1980.2607
X-RAY DIFFRACTIONr_nbd_other0.2070.22165
X-RAY DIFFRACTIONr_nbtor_refined0.1870.21478
X-RAY DIFFRACTIONr_nbtor_other0.0890.21611
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1390.237
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2370.218
X-RAY DIFFRACTIONr_symmetry_vdw_other0.240.272
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1340.29
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.0651871
X-RAY DIFFRACTIONr_mcbond_other0.0245767
X-RAY DIFFRACTIONr_mcangle_it0.08263027
X-RAY DIFFRACTIONr_scbond_it0.07861196
X-RAY DIFFRACTIONr_scangle_it0.0977.51143
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.25→2.31 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.376 97 -
Rwork0.275 1739 -
obs--100 %

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