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

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Basic information

Entry
Database: PDB / ID: 4trw
TitleStructure of BACE1 complex with a syn-HEA-type inhibitor
Components
  • Beta-secretase 1
  • L-alpha-glutamyl-L-isoleucyl-N-[(2R,3S)-1-{[(1S)-1-carboxybutyl]amino}-2-hydroxy-5-methylhexan-3-yl]-3-thiophen-2-yl-L-alaninamide
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 / amyloid-beta metabolic process / 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 / cellular response to manganese ion / amyloid-beta metabolic process / 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 / hippocampal mossy fiber to CA3 synapse / multivesicular body / 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 / lysosome / early endosome / 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
BETA-SECRETASE1 INHIBITOR / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.85 Å
Model detailssyn-HEA, aki213a
AuthorsAkaji, K. / Teruya, K. / Akiyama, T. / Sanjho, A. / Yamashita, E. / Nakagawa, A.
CitationJournal: Bioorg.Med.Chem. / Year: 2015
Title: Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors
Authors: Hattori, Y. / Kobayashi, K. / Deguchi, A. / Nohara, Y. / Akiyama, T. / Teruya, K. / Sanjoh, A. / Nakagawa, A. / Yamashita, E. / Akaji, K.
History
DepositionJun 18, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jul 1, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 8, 2015Group: Derived calculations
Revision 1.2Sep 2, 2015Group: Database references
Revision 1.3Sep 9, 2015Group: Database references
Revision 1.4Jan 29, 2020Group: Data collection / Database references / Derived calculations
Category: citation / diffrn_source / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation
Revision 1.5Nov 8, 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 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / pdbx_validate_peptide_omega / pdbx_validate_rmsd_angle / pdbx_validate_torsion / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _struct_conn.ptnr2_label_atom_id

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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: L-alpha-glutamyl-L-isoleucyl-N-[(2R,3S)-1-{[(1S)-1-carboxybutyl]amino}-2-hydroxy-5-methylhexan-3-yl]-3-thiophen-2-yl-L-alaninamide
E: L-alpha-glutamyl-L-isoleucyl-N-[(2R,3S)-1-{[(1S)-1-carboxybutyl]amino}-2-hydroxy-5-methylhexan-3-yl]-3-thiophen-2-yl-L-alaninamide
F: L-alpha-glutamyl-L-isoleucyl-N-[(2R,3S)-1-{[(1S)-1-carboxybutyl]amino}-2-hydroxy-5-methylhexan-3-yl]-3-thiophen-2-yl-L-alaninamide


Theoretical massNumber of molelcules
Total (without water)132,2036
Polymers132,2036
Non-polymers00
Water88349
1
A: Beta-secretase 1
D: L-alpha-glutamyl-L-isoleucyl-N-[(2R,3S)-1-{[(1S)-1-carboxybutyl]amino}-2-hydroxy-5-methylhexan-3-yl]-3-thiophen-2-yl-L-alaninamide


Theoretical massNumber of molelcules
Total (without water)44,0682
Polymers44,0682
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-5 kcal/mol
Surface area16440 Å2
MethodPISA
2
B: Beta-secretase 1
E: L-alpha-glutamyl-L-isoleucyl-N-[(2R,3S)-1-{[(1S)-1-carboxybutyl]amino}-2-hydroxy-5-methylhexan-3-yl]-3-thiophen-2-yl-L-alaninamide


Theoretical massNumber of molelcules
Total (without water)44,0682
Polymers44,0682
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1260 Å2
ΔGint-5 kcal/mol
Surface area16220 Å2
MethodPISA
3
C: Beta-secretase 1
F: L-alpha-glutamyl-L-isoleucyl-N-[(2R,3S)-1-{[(1S)-1-carboxybutyl]amino}-2-hydroxy-5-methylhexan-3-yl]-3-thiophen-2-yl-L-alaninamide


Theoretical massNumber of molelcules
Total (without water)44,0682
Polymers44,0682
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1240 Å2
ΔGint-3 kcal/mol
Surface area16500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.285, 103.661, 102.000
Angle α, β, γ (deg.)90.000, 102.730, 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: 43425.961 Da / Num. of mol.: 3 / Fragment: UNP residues 58-447
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Plasmid: pET11a / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P56817, memapsin 2
#2: Protein/peptide L-alpha-glutamyl-L-isoleucyl-N-[(2R,3S)-1-{[(1S)-1-carboxybutyl]amino}-2-hydroxy-5-methylhexan-3-yl]-3-thiophen-2-yl-L-alaninamide


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 641.819 Da / Num. of mol.: 3 / Source method: obtained synthetically / Details: designed and chemically synthesized / Source: (synth.) synthetic construct (others) / References: BETA-SECRETASE1 INHIBITOR
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 49 / 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: 3.26 Å3/Da / Density % sol: 62.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 100mM Sodium citrate, 200mM Ammonium sulfate, 14%(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: May 10, 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: 158067 / Rmerge(I) obs: 0.097 / Χ2: 1.11 / D res high: 2.85 Å / D res low: 50 Å / Num. obs: 38857 / % possible obs: 100
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsChi squaredRedundancy
7.735010.0350.9283.9
6.147.7310.0460.8514
5.366.1410.0590.9754.1
4.875.3610.0751.4324.1
4.524.8710.0731.4714.1
4.264.5210.0711.0974.1
4.044.2610.0730.9654.1
3.874.0410.0871.0614.1
3.723.8710.1041.1024.1
3.593.7210.1321.2514.1
3.483.5910.1531.2564.1
3.383.4810.1811.2114.1
3.293.3810.2251.1234.1
3.213.2910.2631.084.1
3.143.2110.3021.0964.1
3.073.1410.3641.0784.1
3.013.0710.4021.0614.1
2.953.0110.4921.0984.1
2.92.9510.5951.1084.1
2.852.910.6691.0224.1
ReflectionResolution: 2.85→50 Å / Num. obs: 38857 / % possible obs: 100 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.097 / Χ2: 1.114 / Net I/av σ(I): 15.904 / Net I/σ(I): 6.6 / Num. measured all: 158067
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.85-2.94.10.66919321.022100
2.9-2.954.10.59519191.108100
2.95-3.014.10.49219171.098100
3.01-3.074.10.40219511.061100
3.07-3.144.10.36419271.078100
3.14-3.214.10.30219411.096100
3.21-3.294.10.26319451.08100
3.29-3.384.10.22519141.123100
3.38-3.484.10.18119331.211100
3.48-3.594.10.15319311.256100
3.59-3.724.10.13219451.251100
3.72-3.874.10.10419491.102100
3.87-4.044.10.08719221.061100
4.04-4.264.10.07319390.965100
4.26-4.524.10.07119591.097100
4.52-4.874.10.07319421.471100
4.87-5.364.10.07519601.432100
5.36-6.144.10.05919460.975100
6.14-7.7340.04619730.851100
7.73-503.90.03520120.92899.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALEPACKdata reduction
HKL-2000data collection
REFMAC5.7.0032refinement
PDB_EXTRACT3.14data extraction
MOLREPmodel building
HKLdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QP8

2qp8


Resolution: 2.85→49.72 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.914 / SU B: 28.704 / SU ML: 0.263 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.349 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2384 1950 5 %RANDOM
Rwork0.2076 36877 --
obs-38827 99.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 209.07 Å2 / Biso mean: 55.86 Å2 / Biso min: 24.96 Å2
Baniso -1Baniso -2Baniso -3
1--0 Å2-0 Å20.03 Å2
2---0.01 Å2-0 Å2
3---0.01 Å2
Refinement stepCycle: final / Resolution: 2.85→49.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9304 0 73 49 9426
Biso mean--50.85 55.64 -
Num. residues----1175
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.029547
X-RAY DIFFRACTIONr_bond_other_d0.0030.028886
X-RAY DIFFRACTIONr_angle_refined_deg1.6651.95612983
X-RAY DIFFRACTIONr_angle_other_deg0.9783.00820422
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.98251165
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.65823.958432
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.592151497
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1291551
X-RAY DIFFRACTIONr_chiral_restr0.0840.21422
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02110840
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022254
X-RAY DIFFRACTIONr_mcbond_it4.0725.5044678
X-RAY DIFFRACTIONr_mcbond_other4.0725.5044676
X-RAY DIFFRACTIONr_mcangle_it6.5988.2485837
LS refinement shellResolution: 2.85→2.923 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.358 129 -
Rwork0.273 2404 -
all-2533 -
obs--88.54 %
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)
10.763-0.04990.08071.2745-0.45840.3591-0.16790.00980.06520.05110.14710.0951-0.11310.03290.02080.1146-0.0074-0.03950.08560.0090.0457-7.53550.865620.733
20.53470.3373-0.23591.0072-0.36380.85640.1246-0.0609-0.02050.0066-0.0727-0.0078-0.021-0.0789-0.0520.04010.005-0.00430.09970.01910.0676-30.1619-38.91642.8189
31.9755-0.4982-0.23440.25370.10130.9610.0324-0.0296-0.3903-0.045-0.00490.15450.03260.1188-0.02760.0715-0.0053-0.01470.0268-0.01420.123818.0009-41.9618.2096
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A59 - 447
2X-RAY DIFFRACTION2B59 - 447
3X-RAY DIFFRACTION3C58 - 447

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