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- PDB-3fkt: Crystal Structure of Human Beta Secretase Complexed with Spiropip... -

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Basic information

Entry
Database: PDB / ID: 3fkt
TitleCrystal Structure of Human Beta Secretase Complexed with Spiropiperdine Iminohydantoin Inhibitor
ComponentsBeta-secretase 1
KeywordsHYDROLASE / ASPARTYL PROTEASE / BACE / Alternative splicing / Glycoprotein / Membrane / Polymorphism / Protease / Transmembrane / Zymogen
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / hippocampal mossy fiber to CA3 synapse / multivesicular body / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / axon / neuronal cell body / dendrite / Golgi apparatus / enzyme binding / cell surface / 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-SII / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsMunshi, S.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Discovery and X-ray Crystallographic Analysis of a Iminohydantoin Inhibitor of beta-Secretase
Authors: Barrow, J.C. / Stauffer, S.R. / Rittle, K.E. / Ngo, P.L. / Yang, M.S. / Graham, S. / McGaughey, G. / Holloway, K. / Tugusheva, S.K. / Lai, M. / Espeseth, A.S. / Xu, M. / Huang, Q. / Zuck, P. ...Authors: Barrow, J.C. / Stauffer, S.R. / Rittle, K.E. / Ngo, P.L. / Yang, M.S. / Graham, S. / McGaughey, G. / Holloway, K. / Tugusheva, S.K. / Lai, M. / Espeseth, A.S. / Xu, M. / Huang, Q. / Zuck, P. / Levorse, D.A. / Hazuda, D. / Vacca, J.P.
History
DepositionDec 17, 2008Deposition site: RCSB / Processing site: RCSB
SupersessionJan 20, 2009ID: 3E3W
Revision 1.0Jan 20, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3Oct 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 1.4Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)45,6142
Polymers45,1231
Non-polymers4921
Water6,161342
1
A: Beta-secretase 1
hetero molecules

A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,2294
Polymers90,2462
Non-polymers9832
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_655-x+1,y,-z+1/21
Buried area3480 Å2
ΔGint-3 kcal/mol
Surface area29780 Å2
MethodPISA
2


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.743, 128.042, 76.768
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-709-

HOH

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Components

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


Mass: 45122.750 Da / Num. of mol.: 1 / Fragment: PROTEASE DOMAIN (RESIDUES 43-446) / Mutation: K95A,E97A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Plasmid: PET11A / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-SII / N-(4-{[4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-8-yl]methyl}phenyl)acetamide


Mass: 491.600 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H34FN5O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 342 / Source method: isolated from a natural source / Formula: H2O

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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: 2.83 Å3/Da / Density % sol: 56.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5
Details: 1.5M LITHIUM SULFATE, 0.1M HEPES BUFFER, VAPOR DIFFUSION, SITTING DROP, TEMPERATURE 293K, PH 7.50. Crystals were grown with L124671 and spiropiperdine iminoh was back soaked in the crystal at pH 5.0, pH 5.00

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5413
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5413 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 40623 / % possible obs: 99.9 % / Redundancy: 6.8 % / Rsym value: 0.067
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 6.3 % / Mean I/σ(I) obs: 2.4 / Rsym value: 0.568 / % possible all: 99.8

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Processing

Software
NameVersionClassification
CCP4Packagemodel building
REFMAC5.2.0019refinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CCP4Packagephasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1TQF

1tqf


Resolution: 1.9→42.99 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.946 / SU B: 2.899 / SU ML: 0.085 / Cross valid method: THROUGHOUT / ESU R: 0.126 / ESU R Free: 0.122 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21663 2034 5 %RANDOM
Rwork0.1816 ---
obs0.18332 38567 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.33 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20 Å2
2---0.01 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.9→42.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2895 0 36 342 3273
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0223011
X-RAY DIFFRACTIONr_angle_refined_deg1.4381.9624097
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.555368
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.76823.731134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.38115471
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6881517
X-RAY DIFFRACTIONr_chiral_restr0.0960.2440
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022304
X-RAY DIFFRACTIONr_nbd_refined0.2030.21375
X-RAY DIFFRACTIONr_nbtor_refined0.310.22016
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1630.2277
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2020.265
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3660.228
X-RAY DIFFRACTIONr_mcbond_it0.9171.51881
X-RAY DIFFRACTIONr_mcangle_it1.51622962
X-RAY DIFFRACTIONr_scbond_it2.10931310
X-RAY DIFFRACTIONr_scangle_it3.3314.51135
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 166 -
Rwork0.308 2796 -
obs--99.2 %

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