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- PDB-6jt4: Crystal Structure of BACE1 in complex with N-{3-[(4S,6S)-2-amino-... -

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Basic information

Entry
Database: PDB / ID: 6jt4
TitleCrystal Structure of BACE1 in complex with N-{3-[(4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide
ComponentsBeta-secretase 1
KeywordsHYDROLASE / GS-hBACE1(43-454)
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 / cellular response to manganese ion / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain ...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 / cellular response to manganese ion / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to copper ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / response to lead ion / 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 / endosome membrane / 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
Chem-C86 / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsAnan, K. / Iso, Y. / Oguma, T. / Nakahara, K. / Suzuki, S. / Yamamoto, T. / Matsuoka, E. / Ito, H. / Sakaguchi, G. / Ando, S. ...Anan, K. / Iso, Y. / Oguma, T. / Nakahara, K. / Suzuki, S. / Yamamoto, T. / Matsuoka, E. / Ito, H. / Sakaguchi, G. / Ando, S. / Morimoto, K. / Kanegawa, N. / Kido, Y. / Kawachi, T. / Fukushima, T. / Teisman, A. / Urmaliya, V. / Dhuyvetter, D. / Borghys, H. / Austin, N. / Bergh, A.V.D. / Verboven, P. / Bischoff, F. / Gijsen, H.J.M. / Yamano, Y. / Kusakabe, K.I.
CitationJournal: Chemmedchem / Year: 2019
Title: Trifluoromethyl Dihydrothiazine-Based beta-Secretase (BACE1) Inhibitors with Robust Central beta-Amyloid Reduction and Minimal Covalent Binding Burden.
Authors: Anan, K. / Iso, Y. / Oguma, T. / Nakahara, K. / Suzuki, S. / Yamamoto, T. / Matsuoka, E. / Ito, H. / Sakaguchi, G. / Ando, S. / Morimoto, K. / Kanegawa, N. / Kido, Y. / Kawachi, T. / ...Authors: Anan, K. / Iso, Y. / Oguma, T. / Nakahara, K. / Suzuki, S. / Yamamoto, T. / Matsuoka, E. / Ito, H. / Sakaguchi, G. / Ando, S. / Morimoto, K. / Kanegawa, N. / Kido, Y. / Kawachi, T. / Fukushima, T. / Teisman, A. / Urmaliya, V. / Dhuyvetter, D. / Borghys, H. / Austin, N. / Van Den Bergh, A. / Verboven, P. / Bischoff, F. / Gijsen, H.J.M. / Yamano, Y. / Kusakabe, K.
History
DepositionApr 8, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 15, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 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 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)47,4197
Polymers46,3931
Non-polymers1,0266
Water3,675204
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: fluorescence resonance energy transfer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-1 kcal/mol
Surface area15580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.590, 101.590, 170.351
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


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


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-C86 / N-[3-[(4S,6S)-2-azanyl-4-methyl-6-(trifluoromethyl)-5,6-dihydro-1,3-thiazin-4-yl]-4-fluoranyl-phenyl]-5-(fluoranylmethoxy)pyrazine-2-carboxamide


Mass: 461.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16F5N5O2S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 204 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.73 Å3/Da / Density % sol: 59.96 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2 M sodium citrate tribasic pH 6.5, 0.2 M ammonium iodide, 20.5% w/v PEG 5000MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Dec 14, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.2→56.78 Å / Num. obs: 27088 / % possible obs: 99.9 % / Redundancy: 8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.033 / Rrim(I) all: 0.096 / Net I/σ(I): 7.8
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
2.2-2.278.10.4481850522770.9240.1650.4783.499.6
9.07-56.7860.03528464780.9970.0150.03810.499

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Processing

Software
NameVersionClassification
Aimlessdata extraction
MOSFLMdata processing
MOLREPphasing
REFMAC5.8.0218refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1W50

1w50


Resolution: 2.2→20 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.921 / SU B: 4.806 / SU ML: 0.123 / SU R Cruickshank DPI: 0.2129 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.213 / ESU R Free: 0.183
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2339 1407 5.2 %RANDOM
Rwork0.1951 ---
obs0.1972 25639 99.82 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 88.44 Å2 / Biso mean: 31.602 Å2 / Biso min: 15.31 Å2
Baniso -1Baniso -2Baniso -3
1--0 Å2-0 Å2-0 Å2
2---0 Å2-0 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2862 0 46 204 3112
Biso mean--37.51 36.9 -
Num. residues----370
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0192986
X-RAY DIFFRACTIONr_bond_other_d0.0030.022666
X-RAY DIFFRACTIONr_angle_refined_deg1.3291.9354061
X-RAY DIFFRACTIONr_angle_other_deg0.7622.9896153
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7475367
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.54423.308133
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.99915449
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.7441516
X-RAY DIFFRACTIONr_chiral_restr0.2530.2448
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213321
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02641
LS refinement shellResolution: 2.2→2.257 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.229 99 -
Rwork0.206 1857 -
all-1956 -
obs--99.34 %

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