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- PDB-5ygy: Crystal Structure of BACE1 in complex with (S)-N-(3-(2-amino-6-(f... -

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Basic information

Entry
Database: PDB / ID: 5ygy
TitleCrystal Structure of BACE1 in complex with (S)-N-(3-(2-amino-6-(fluoromethyl)-4 -methyl-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide
ComponentsBeta-secretase 1
KeywordsHYDROLASE/INHIBITOR / beta-site amyloid precursor protein cleaving enzyme 1 / HYDROLASE-INHIBITOR complex
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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / protein serine/threonine kinase binding / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / multivesicular body / hippocampal mossy fiber to CA3 synapse / response to lead ion / trans-Golgi network / recycling endosome / protein processing / 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 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-0B6 / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsFuchino, K. / Mitsuoka, Y. / Masui, M. / Kurose, N. / Yoshida, S. / Komano, K. / Yamamoto, T. / Ogawa, M. / Unemura, C. / Hosono, M. ...Fuchino, K. / Mitsuoka, Y. / Masui, M. / Kurose, N. / Yoshida, S. / Komano, K. / Yamamoto, T. / Ogawa, M. / Unemura, C. / Hosono, M. / Ito, H. / Sakaguchi, G. / Ando, S. / Ohnishi, S. / Kido, Y. / Fukushima, T. / Miyajima, H. / Hiroyama, S. / Koyabu, K. / Dhuyvetter, D. / Borghys, H. / Gijsen, H. / Yamano, Y. / Iso, Y. / Kusakabe, K.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Rational Design of Novel 1,3-Oxazine Based beta-Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P-gp Efflux Leading to Robust A beta Reduction in the Brain
Authors: Fuchino, K. / Mitsuoka, Y. / Masui, M. / Kurose, N. / Yoshida, S. / Komano, K. / Yamamoto, T. / Ogawa, M. / Unemura, C. / Hosono, M. / Ito, H. / Sakaguchi, G. / Ando, S. / Ohnishi, S. / ...Authors: Fuchino, K. / Mitsuoka, Y. / Masui, M. / Kurose, N. / Yoshida, S. / Komano, K. / Yamamoto, T. / Ogawa, M. / Unemura, C. / Hosono, M. / Ito, H. / Sakaguchi, G. / Ando, S. / Ohnishi, S. / Kido, Y. / Fukushima, T. / Miyajima, H. / Hiroyama, S. / Koyabu, K. / Dhuyvetter, D. / Borghys, H. / Gijsen, H.J.M. / Yamano, Y. / Iso, Y. / Kusakabe, K.I.
History
DepositionSep 27, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 23, 2018Provider: repository / Type: Initial release
Revision 1.1May 30, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Jul 11, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Nov 22, 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
Revision 1.4Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)47,68710
Polymers46,3931
Non-polymers1,2949
Water3,585199
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area280 Å2
ΔGint-1 kcal/mol
Surface area15950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.149, 102.149, 171.125
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 / Fragment: UNP residues 43-454
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


Mass: 126.904 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-0B6 / ~{N}-[3-[(4~{S})-2-azanyl-6-(fluoranylmethyl)-4-methyl-1,3-oxazin-4-yl]-4-fluoranyl-phenyl]-5-cyano-pyridine-2-carboxamide


Mass: 383.352 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15F2N5O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 199 / 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: 3.03 Å3/Da / Density % sol: 59.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.2M sodium citrate tribasic pH6.5, 0.2M ammonium iodide, 20.5%(w/v) PEG5000MME

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Aug 6, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 24045 / % possible obs: 99.3 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.1 / Χ2: 1.179 / Net I/σ(I): 8.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.3-2.345.50.52911800.762199.7
2.34-2.385.50.49511720.762199.6
2.38-2.435.50.45511780.768199.8
2.43-2.485.50.40911790.777199.8
2.48-2.535.50.37211810.793199.7
2.53-2.595.50.32211890.862199.9
2.59-2.665.50.29111690.845199.8
2.66-2.735.50.27311980.865199.8
2.73-2.815.50.23711970.9281100
2.81-2.95.50.20711821.0151100
2.9-35.50.16512051.058199.9
3-3.125.50.13911851.158199.7
3.12-3.265.50.12111981.252199.8
3.26-3.445.50.10112161.317199.7
3.44-3.655.50.07912051.487199.5
3.65-3.935.40.06412121.6199.5
3.93-4.335.40.05712191.665199.1
4.33-4.955.30.04912191.777198.7
4.95-6.245.30.05412521.778197.8
6.24-504.80.04413092.124194.2

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3 Å32.82 Å
Translation32.82 Å3 Å

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Processing

Software
NameVersionClassification
HKL-2000data processing
HKL-2000data scaling
MOLREPphasing
REFMAC5.8.0158refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1W50

1w50


Resolution: 2.3→20 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.922 / SU B: 6.179 / SU ML: 0.149 / SU R Cruickshank DPI: 0.2747 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.275 / ESU R Free: 0.216
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2354 2428 10.1 %RANDOM
Rwork0.1912 ---
obs0.1957 21583 99.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 152.27 Å2 / Biso mean: 40.327 Å2 / Biso min: 20.82 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å20.03 Å20 Å2
2--0.07 Å20 Å2
3----0.21 Å2
Refinement stepCycle: final / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2940 0 51 199 3190
Biso mean--55.51 41.23 -
Num. residues----381
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0193063
X-RAY DIFFRACTIONr_angle_refined_deg1.4941.9544165
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0535379
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.35823.582134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.20615456
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5841517
X-RAY DIFFRACTIONr_chiral_restr0.10.2454
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212347
LS refinement shellResolution: 2.3→2.359 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 179 -
Rwork0.239 1539 -
all-1718 -
obs--99.48 %

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