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- PDB-7d5a: Crystal Structure of BACE1 in complex with N-{3-[(9S)-7-amino-2,2... -

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Basic information

Entry
Database: PDB / ID: 7d5a
TitleCrystal Structure of BACE1 in complex with N-{3-[(9S)-7-amino-2,2-difluoro-9-(prop-1-yn-1-yl)-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluorophenyl}-5-cyanopyridine-2-carboxamide
ComponentsBeta-secretase 1
KeywordsHYDROLASE / BACE1
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. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily
Similarity search - Domain/homology
Chem-GX6 / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 Å
AuthorsFujimoto, K. / Yoshida, S. / Tadano, G. / Asada, N. / Fuchino, K. / Suzuki, S. / Matsuoka, E. / Yamamoto, T. / Yamamoto, S. / Ando, S. ...Fujimoto, K. / Yoshida, S. / Tadano, G. / Asada, N. / Fuchino, K. / Suzuki, S. / Matsuoka, E. / Yamamoto, T. / Yamamoto, S. / Ando, S. / Kanegawa, N. / Tonomura, Y. / Ito, H. / Moechars, D. / Rombouts, F.J.R. / Gijsen, H.J.M. / Kusakabe, K.I.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective beta-Secretase (BACE1) Inhibitors over BACE2.
Authors: Fujimoto, K. / Yoshida, S. / Tadano, G. / Asada, N. / Fuchino, K. / Suzuki, S. / Matsuoka, E. / Yamamoto, T. / Yamamoto, S. / Ando, S. / Kanegawa, N. / Tonomura, Y. / Ito, H. / Moechars, D. ...Authors: Fujimoto, K. / Yoshida, S. / Tadano, G. / Asada, N. / Fuchino, K. / Suzuki, S. / Matsuoka, E. / Yamamoto, T. / Yamamoto, S. / Ando, S. / Kanegawa, N. / Tonomura, Y. / Ito, H. / Moechars, D. / Rombouts, F.J.R. / Gijsen, H.J.M. / Kusakabe, K.I.
History
DepositionSep 25, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 31, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)47,1925
Polymers46,3931
Non-polymers7994
Water4,216234
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area190 Å2
ΔGint-0 kcal/mol
Surface area15260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.100, 102.100, 170.041
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

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


Mass: 46393.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-GX6 / N-[3-[(9S)-7-azanyl-2,2-bis(fluoranyl)-9-prop-1-ynyl-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluoranyl-phenyl]-5-cyano-pyridine-2-carboxamide


Mass: 453.417 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H18F3N5O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 234 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.76 Å3/Da / Density % sol: 55.39 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.2 M sodium citrate tribasic pH6.5, 0.2 M ammonium iodide, 18% w/v PEG 5000MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54178 Å
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Nov 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.2→44.21 Å / Num. obs: 27297 / % possible obs: 99.9 % / Redundancy: 7 % / CC1/2: 0.997 / Rmerge(I) obs: 0.107 / Rpim(I) all: 0.043 / Rrim(I) all: 0.116 / Net I/σ(I): 12.7 / Num. measured all: 191485 / Scaling rejects: 309
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.2-2.277.10.5071639323230.8910.2020.5473.999.5
9.07-44.215.60.03626924780.9990.0160.0392398.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.371
Highest resolutionLowest resolution
Rotation39.23 Å3 Å
Translation39.23 Å3 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
Aimless0.5.15data scaling
MOLREPphasing
REFMAC5.8.0131refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1W50

1w50


Resolution: 2.2→20 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.918 / SU B: 5.398 / SU ML: 0.136 / SU R Cruickshank DPI: 0.2235 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.223 / ESU R Free: 0.189 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2424 1368 5 %RANDOM
Rwork0.2069 ---
obs0.2087 25842 99.59 %-
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 max: 78.39 Å2 / Biso mean: 35.923 Å2 / Biso min: 18.89 Å2
Baniso -1Baniso -2Baniso -3
1-0.11 Å20.05 Å20 Å2
2--0.11 Å2-0 Å2
3----0.35 Å2
Refinement stepCycle: final / Resolution: 2.2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2836 0 41 234 3111
Biso mean--42.32 39.72 -
Num. residues----365
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0192951
X-RAY DIFFRACTIONr_angle_refined_deg1.3961.9394014
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.795361
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.03123.664131
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.22415446
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8891516
X-RAY DIFFRACTIONr_chiral_restr0.0870.2435
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212248
LS refinement shellResolution: 2.2→2.256 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.294 107 -
Rwork0.234 1827 -
all-1934 -
obs--99.28 %

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