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- PDB-7d36: Crystal Structure of BACE1 in complex with N-{3-[(3S)-1-amino-5-f... -

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Basic information

Entry
Database: PDB / ID: 7d36
TitleCrystal Structure of BACE1 in complex with N-{3-[(3S)-1-amino-5-fluoro-3-methyl-3,4-dihydro-2,6-naphthyridin-3-yl]-4-fluorophenyl}-5-cyano-3-methylpyridine-2-carboxamide
ComponentsBeta-secretase 1
KeywordsHYDROLASE / BACE1
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 / cellular response to manganese ion / 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / late endosome / synaptic vesicle / 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 / Amyloid fiber formation / membrane raft / endoplasmic reticulum lumen / 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. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily
Similarity search - Domain/homology
Chem-GUC / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsNakahara, K. / Mitsuoka, Y. / Kasuya, S. / Yamamoto, T. / Yamamoto, S. / Ito, H. / Kido, Y. / Kusakabe, K.I.
CitationJournal: Eur.J.Med.Chem. / Year: 2021
Title: Balancing potency and basicity by incorporating fluoropyridine moieties: Discovery of a 1-amino-3,4-dihydro-2,6-naphthyridine BACE1 inhibitor that affords robust and sustained central A beta reduction.
Authors: Nakahara, K. / Mitsuoka, Y. / Kasuya, S. / Yamamoto, T. / Yamamoto, S. / Ito, H. / Kido, Y. / Kusakabe, K.I.
History
DepositionSep 18, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 28, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 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
Revision 1.2Nov 13, 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)47,6099
Polymers46,3931
Non-polymers1,2168
Water3,099172
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1260 Å2
ΔGint0 kcal/mol
Surface area15630 Å2
Unit cell
Length a, b, c (Å)102.531, 102.531, 170.115
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.: 4 / 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-GUC / N-[3-[(3S)-1-azanyl-5-fluoranyl-3-methyl-4H-2,6-naphthyridin-3-yl]-4-fluoranyl-phenyl]-5-cyano-3-methyl-pyridine-2-carboxamide


Mass: 432.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H18F2N6O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 172 / 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: 2.78 Å3/Da / Density % sol: 55.79 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2 M sodium citrate tribasic pH 6.5, 0.2 M ammonium iodide, 18.6% 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: Apr 17, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 24130 / % possible obs: 99.5 % / Redundancy: 8.3 % / Rmerge(I) obs: 0.094 / Χ2: 1.062 / Net I/σ(I): 8.9 / Num. measured all: 199629
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.3-2.348.40.5211890.73199.3
2.34-2.388.50.47711510.732199.4
2.38-2.438.40.47311770.762199.2
2.43-2.488.40.39311660.747199.3
2.48-2.538.50.3711780.756199.7
2.53-2.598.40.31311910.794199.3
2.59-2.668.40.28611740.808199.7
2.66-2.738.40.26511850.836199.6
2.73-2.818.40.23111900.812199.7
2.81-2.98.40.19111930.896199.8
2.9-38.40.15512030.966199.8
3-3.128.40.1311981.041199.8
3.12-3.268.40.10912001.064199.9
3.26-3.448.30.09712161.1881100
3.44-3.658.30.07212181.31100
3.65-3.938.20.06112191.4611100
3.93-4.338.20.05312331.46199.7
4.33-4.958.10.04412411.477199.6
4.95-6.2480.04912591.518199.3
6.24-507.30.04113491.902196.4

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3 Å47.79 Å
Translation47.79 Å3 Å

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
REFMAC5.5.0102refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1W50

1w50


Resolution: 2.3→20 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.901 / SU B: 6.533 / SU ML: 0.161 / SU R Cruickshank DPI: 0.2976 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.298 / ESU R Free: 0.241 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2652 2437 10.1 %RANDOM
Rwork0.2129 ---
obs0.2181 21623 99.67 %-
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: 86.45 Å2 / Biso mean: 44.425 Å2 / Biso min: 23.72 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20.01 Å20 Å2
2--0.01 Å20 Å2
3----0.02 Å2
Refinement stepCycle: final / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2902 0 54 172 3128
Biso mean--55.47 45.27 -
Num. residues----378
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0223030
X-RAY DIFFRACTIONr_angle_refined_deg1.3631.964125
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7415376
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.16223.385130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.29915445
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8781517
X-RAY DIFFRACTIONr_chiral_restr0.0870.2444
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212337
LS refinement shellResolution: 2.3→2.359 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.278 174 -
Rwork0.237 1541 -
all-1715 -
obs--99.42 %

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