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- PDB-7d2v: Crystal Structure of BACE1 in complex with N-{3-[(5R)-3-amino-2,5... -

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Basic information

Entry
Database: PDB / ID: 7d2v
TitleCrystal Structure of BACE1 in complex with N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-5,6-dihydro-2H-1lambda6,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-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 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 / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / 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 / cellular response to copper ion / protein serine/threonine kinase binding / presynaptic modulation of chemical synaptic transmission / multivesicular body / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / response to lead ion / protein processing / recycling endosome / 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 / Amyloid fiber formation / 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-66F / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 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 17, 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
Revision 1.3Oct 16, 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)47,3677
Polymers46,3931
Non-polymers9746
Water4,161231
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area950 Å2
ΔGint0 kcal/mol
Surface area16020 Å2
Unit cell
Length a, b, c (Å)102.720, 102.720, 170.591
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-66F / N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide


Mass: 409.410 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17F2N5O3S / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / 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: 2.8 Å3/Da / Density % sol: 56.07 %
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, 19.5% w/v PEG 5000MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Nov 12, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.1→40 Å / Num. obs: 31499 / % possible obs: 99.4 % / Redundancy: 10.5 % / Rmerge(I) obs: 0.098 / Net I/σ(I): 16.4
Reflection shellResolution: 2.1→2.21 Å / Rmerge(I) obs: 0.538 / Num. unique obs: 31499

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation38.46 Å3 Å
Translation38.46 Å3 Å

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Processing

Software
NameVersionClassification
HKL-2000data scaling
MOLREPphasing
REFMAC5.7.0029refinement
PDB_EXTRACT3.25data extraction
Aimlessdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1W50

1w50


Resolution: 2.1→20 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.921 / SU B: 4.505 / SU ML: 0.121 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.205 / ESU R Free: 0.18 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2453 3154 10 %RANDOM
Rwork0.2062 ---
obs0.2102 28330 99.13 %-
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: 83.77 Å2 / Biso mean: 36.192 Å2 / Biso min: 16.56 Å2
Baniso -1Baniso -2Baniso -3
1--0.13 Å2-0.13 Å2-0 Å2
2---0.13 Å2-0 Å2
3---0.41 Å2
Refinement stepCycle: final / Resolution: 2.1→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2935 0 43 231 3209
Biso mean--37.66 39.2 -
Num. residues----379
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0193053
X-RAY DIFFRACTIONr_angle_refined_deg1.2331.9584158
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4835377
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.0823.433134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.60915459
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5931518
X-RAY DIFFRACTIONr_chiral_restr0.0820.2453
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212352
LS refinement shellResolution: 2.1→2.154 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.286 198 -
Rwork0.247 2013 -
all-2211 -
obs--98.05 %

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