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- PDB-4try: Structure of BACE1 complex with a HEA-type inhibitor -

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Basic information

Entry
Database: PDB / ID: 4try
TitleStructure of BACE1 complex with a HEA-type inhibitor
Components
  • Beta-secretase 1
  • GLU-ILE-TIH-THC-NVA
KeywordsHYDROLASE/HYDROLASE INHIBITOR / hydrase proteinase converting / designed inhibitor / hydrase-inhibitor complex / HYDROLASE-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 / cellular response to manganese ion / prepulse inhibition / amyloid-beta metabolic process ...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 / prepulse inhibition / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / multivesicular body / response to lead ion / trans-Golgi network / protein processing / recycling endosome / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / dendrite / neuronal cell body / 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
syn-HEA type inhibitor / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.75 Å
Model detailssyn-HEA, aki213a
AuthorsAkaji, K. / Teruya, K. / Akiyama, T. / Sanjho, A. / Yamashita, E. / Nakagawa, A.
CitationJournal: to be published
Title: Structure of BACE1 complex with an anti-HMC-type inhibitor
Authors: Akaji, K. / Teruya, K. / Akiyama, T. / Sanjho, A. / Yamashita, E. / Nakagawa, A.
History
DepositionJun 18, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jul 29, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2020Group: Data collection / Derived calculations / Source and taxonomy
Category: diffrn_source / entity_src_gen ...diffrn_source / entity_src_gen / pdbx_entity_src_syn / pdbx_struct_oper_list
Item: _diffrn_source.pdbx_synchrotron_site / _entity_src_gen.pdbx_alt_source_flag ..._diffrn_source.pdbx_synchrotron_site / _entity_src_gen.pdbx_alt_source_flag / _pdbx_entity_src_syn.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Nov 8, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
C: Beta-secretase 1
D: GLU-ILE-TIH-THC-NVA
E: GLU-ILE-TIH-THC-NVA
F: GLU-ILE-TIH-THC-NVA


Theoretical massNumber of molelcules
Total (without water)131,9336
Polymers131,9336
Non-polymers00
Water77543
1
A: Beta-secretase 1
D: GLU-ILE-TIH-THC-NVA


Theoretical massNumber of molelcules
Total (without water)43,9782
Polymers43,9782
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1270 Å2
ΔGint-5 kcal/mol
Surface area16210 Å2
MethodPISA
2
B: Beta-secretase 1
E: GLU-ILE-TIH-THC-NVA


Theoretical massNumber of molelcules
Total (without water)43,9782
Polymers43,9782
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1250 Å2
ΔGint-4 kcal/mol
Surface area16520 Å2
MethodPISA
3
C: Beta-secretase 1
F: GLU-ILE-TIH-THC-NVA


Theoretical massNumber of molelcules
Total (without water)43,9782
Polymers43,9782
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1230 Å2
ΔGint-5 kcal/mol
Surface area16590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.326, 102.618, 101.287
Angle α, β, γ (deg.)90.000, 103.530, 90.000
Int Tables number4
Space group name H-MP1211

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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: 43281.832 Da / Num. of mol.: 3
Fragment: beta-site amyloid precursor protein-converting enzyme
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Plasmid: pET11a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Protein/peptide GLU-ILE-TIH-THC-NVA / syn-HEA type inhibitor


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 695.847 Da / Num. of mol.: 3 / Source method: obtained synthetically
Details: The peptide was designed and chemically synthesized
Source: (synth.) synthetic construct (others) / References: syn-HEA type inhibitor
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 43 / Source method: isolated from a natural source / Formula: H2O

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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: 3.2 Å3/Da / Density % sol: 61.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 100mM Sodium citrate pH5.0, 200mM Ammonium sulfate, 22% v/v PEG 10000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 0.9 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Jun 27, 2013 / Details: horizontal focusing mirror
RadiationMonochromator: double-crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionRedundancy: 4.1 % / Number: 172450 / Rmerge(I) obs: 0.091 / Χ2: 1.22 / D res high: 2.75 Å / D res low: 50 Å / Num. obs: 42426 / % possible obs: 100
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsChi squaredRedundancy
7.465010.0341.2943.9
5.927.4610.0411.0894
5.175.9210.0461.1134.1
4.75.1710.051.2884.1
4.364.710.0611.7584.1
4.114.3610.0721.7354.1
3.94.1110.0761.4244.1
3.733.910.0831.2674.1
3.593.7310.1021.2654.1
3.463.5910.1191.1994.1
3.363.4610.1531.2184.1
3.263.3610.1971.1764.1
3.173.2610.2311.1394.1
3.13.1710.2761.1284.1
3.033.110.3261.0744.1
2.963.0310.3861.0364.1
2.92.9610.4651.0634.1
2.852.910.5231.0374.1
2.82.8510.6311.0274.1
2.752.810.7591.0434.1
ReflectionResolution: 2.75→50 Å / Num. obs: 42426 / % possible obs: 100 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.091 / Χ2: 1.218 / Net I/av σ(I): 17.067 / Net I/σ(I): 9.1 / Num. measured all: 172450
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.75-2.84.10.75921051.043100
2.8-2.854.10.63121281.027100
2.85-2.94.10.52320961.037100
2.9-2.964.10.46520991.063100
2.96-3.034.10.38621251.036100
3.03-3.14.10.32620911.074100
3.1-3.174.10.27621321.128100
3.17-3.264.10.23121161.139100
3.26-3.364.10.19721081.176100
3.36-3.464.10.15321091.218100
3.46-3.594.10.11921131.199100
3.59-3.734.10.10221391.265100
3.73-3.94.10.08321041.267100
3.9-4.114.10.07621351.424100
4.11-4.364.10.07220961.735100
4.36-4.74.10.06121191.758100
4.7-5.174.10.0521361.288100
5.17-5.924.10.04621431.113100
5.92-7.4640.04121411.089100
7.46-503.90.03421911.29499.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
DENZOdata collection
SCALEPACKdata reduction
REFMAC5.7.0032refinement
PDB_EXTRACT3.14data extraction
MOLREPmodel building
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QP8

2qp8


Resolution: 2.75→49.18 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.904 / SU B: 26.632 / SU ML: 0.252 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.9 / ESU R Free: 0.34 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2517 2139 5 %RANDOM
Rwork0.1795 40264 --
obs0.183 42403 99.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 242.91 Å2 / Biso mean: 54.999 Å2 / Biso min: 25.1 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20.04 Å2
2---0.03 Å2-0 Å2
3---0.01 Å2
Refinement stepCycle: final / Resolution: 2.75→49.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9283 0 90 43 9416
Biso mean--53.07 48.55 -
Num. residues----1169
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.029537
X-RAY DIFFRACTIONr_bond_other_d0.0040.028850
X-RAY DIFFRACTIONr_angle_refined_deg1.6951.95712972
X-RAY DIFFRACTIONr_angle_other_deg0.9873.00720334
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.09251161
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.22823.958432
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.214151494
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8231551
X-RAY DIFFRACTIONr_chiral_restr0.0870.21416
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02110845
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022262
X-RAY DIFFRACTIONr_mcbond_it4.0735.4194662
X-RAY DIFFRACTIONr_mcbond_other4.0745.4194660
X-RAY DIFFRACTIONr_mcangle_it6.6558.125817
LS refinement shellResolution: 2.755→2.826 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.373 167 -
Rwork0.278 2866 -
all-3033 -
obs--96.78 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.51550.058-0.02911.2128-0.17110.2245-0.08280.04380.02610.0170.09370.1011-0.07360.0113-0.01080.0829-0.0062-0.02680.05050.01030.022933.86950.852921.2757
20.64450.247-0.32551.04060.02230.60210.0648-0.03790.00290.093-0.04860.02340.0044-0.0423-0.01620.02950.0061-0.00990.08880.0250.03389.8477-39.084741.3737
31.4849-0.677-0.04990.3269-0.05420.63530.0388-0.046-0.3338-0.02890.00940.1662-0.02680.1386-0.04820.0304-0.0056-0.03250.0524-0.02120.11958.37-41.660816.4591
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A60 - 446
2X-RAY DIFFRACTION1A501 - 510
3X-RAY DIFFRACTION2B60 - 447
4X-RAY DIFFRACTION2B501 - 515
5X-RAY DIFFRACTION3C60 - 447
6X-RAY DIFFRACTION3C501 - 516

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