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- PDB-2oht: X-ray crystal structure of beta secretase complexed with compound 7 -

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Basic information

Entry
Database: PDB / ID: 2oht
TitleX-ray crystal structure of beta secretase complexed with compound 7
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
IODIDE ION / Chem-IP6 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 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 1.0Mar 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_struct_special_symmetry ...database_2 / pdbx_struct_special_symmetry / 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

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,6156
Polymers44,8411
Non-polymers7735
Water3,081171
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.188, 103.188, 169.049
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-708-

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.: 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-IP6 / N~3~-[3-(1H-INDOL-6-YL)BENZYL]PYRIDINE-2,3-DIAMINE


Mass: 314.384 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18N4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / 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: 2.9 Å3/Da / Density % sol: 57.52 %
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: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 0.931 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Nov 23, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.931 Å / Relative weight: 1
ReflectionResolution: 2.3→49.35 Å / Num. all: 22857 / Num. obs: 22857 / % possible obs: 99.4 % / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.105

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0019crefinement
PDB_EXTRACTdata extraction
ProDCdata 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: 2.3→49.35 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.898 / SU B: 7.181 / SU ML: 0.177 / Cross valid method: THROUGHOUT / ESU R: 0.277 / ESU R Free: 0.235 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26945 1225 5.1 %RANDOM
Rwork0.21185 ---
all0.21481 22857 --
obs0.21481 22857 --
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: 34.344 Å2
Baniso -1Baniso -2Baniso -3
1--0.38 Å2-0.19 Å20 Å2
2---0.38 Å20 Å2
3---0.57 Å2
Refinement stepCycle: LAST / Resolution: 2.3→49.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2966 0 31 171 3168
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0223070
X-RAY DIFFRACTIONr_bond_other_d0.0010.022037
X-RAY DIFFRACTIONr_angle_refined_deg1.361.9564175
X-RAY DIFFRACTIONr_angle_other_deg0.8883.0024937
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7715375
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.24923.759141
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.25615482
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2771517
X-RAY DIFFRACTIONr_chiral_restr0.0790.2452
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023435
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02645
X-RAY DIFFRACTIONr_nbd_refined0.1980.2617
X-RAY DIFFRACTIONr_nbd_other0.2040.22204
X-RAY DIFFRACTIONr_nbtor_refined0.1880.21474
X-RAY DIFFRACTIONr_nbtor_other0.0890.21577
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1790.253
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.090.22
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.120.220
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2310.252
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.10.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.05751871
X-RAY DIFFRACTIONr_mcbond_other0.0235767
X-RAY DIFFRACTIONr_mcangle_it0.08163026
X-RAY DIFFRACTIONr_scbond_it0.07661199
X-RAY DIFFRACTIONr_scangle_it0.0967.51149
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 90 -
Rwork0.263 1655 -
obs--99.09 %

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