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- PDB-4trz: Structure of BACE1 complex with 2-thiophenyl HEA-type inhibitor -

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Basic information

Entry
Database: PDB / ID: 4trz
TitleStructure of BACE1 complex with 2-thiophenyl HEA-type inhibitor
Components
  • 2-thiophenyl HEA-type inhibitor
  • Beta-secretase 1
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
2-thiophenyl 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: 3.25 Å
Model detailssyn-HEA, aki092
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 1.1Sep 2, 2015Group: Database references
Revision 1.2Sep 9, 2015Group: Database references
Revision 1.3Jan 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 1.4Nov 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
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_main_chain_plane / pdbx_validate_rmsd_angle / pdbx_validate_rmsd_bond / 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: 2-thiophenyl HEA-type inhibitor
E: 2-thiophenyl HEA-type inhibitor
F: 2-thiophenyl HEA-type inhibitor


Theoretical massNumber of molelcules
Total (without water)131,8916
Polymers131,8916
Non-polymers00
Water19811
1
A: Beta-secretase 1
D: 2-thiophenyl HEA-type inhibitor


Theoretical massNumber of molelcules
Total (without water)43,9642
Polymers43,9642
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1300 Å2
ΔGint-6 kcal/mol
Surface area16490 Å2
MethodPISA
2
B: Beta-secretase 1
E: 2-thiophenyl HEA-type inhibitor


Theoretical massNumber of molelcules
Total (without water)43,9642
Polymers43,9642
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1260 Å2
ΔGint-5 kcal/mol
Surface area16680 Å2
MethodPISA
3
C: Beta-secretase 1
F: 2-thiophenyl HEA-type inhibitor


Theoretical massNumber of molelcules
Total (without water)43,9642
Polymers43,9642
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1310 Å2
ΔGint-6 kcal/mol
Surface area16730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.872, 102.420, 101.587
Angle α, β, γ (deg.)90.000, 103.490, 90.000
Int Tables number4
Space group name H-MP1211
Detailsbiological unit is the same as asym.

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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: UNP residues 60-447
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 2-thiophenyl HEA-type inhibitor


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 681.863 Da / Num. of mol.: 3 / Source method: obtained synthetically / Details: designed and chemically synthesized / Source: (synth.) synthetic construct (others) / References: 2-thiophenyl HEA-type inhibitor
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 11 / 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: 3.19 Å3/Da / Density % sol: 61.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 100mM Sodium citrate, 200mM Ammonium sulfate, 23%(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: Dec 4, 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
ReflectionResolution: 3.16→50 Å / Num. obs: 27835 / % possible obs: 100 % / Redundancy: 3.8 % / Net I/σ(I): 16
Reflection shellResolution: 3.16→3.24 Å / Redundancy: 3.8 % / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
DENZOdata collection
SCALEPACKdata reduction
MOLREPmodel building
REFMAC5.8.0049refinement
PDB_EXTRACT3.14data extraction
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QP8

2qp8


Resolution: 3.25→49.1 Å / Cor.coef. Fo:Fc: 0.88 / Cor.coef. Fo:Fc free: 0.862 / SU ML: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.537 / ESU R Free: 0.603 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2951 1315 5.1 %RANDOM
Rwork0.2631 24467 --
obs0.2647 25782 99.22 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 275.33 Å2 / Biso min: 20 Å2
Baniso -1Baniso -2Baniso -3
1-0.09 Å2-0 Å20.24 Å2
2---0.49 Å20 Å2
3---0.25 Å2
Refinement stepCycle: final / Resolution: 3.25→49.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9288 0 79 11 9378
Biso mean--20 52.95 -
Num. residues----1171
LS refinement shellResolution: 3.246→3.33 Å
RfactorNum. reflection% reflection
Rfree0.402 90 -
Rwork-1652 -
obs--91.35 %

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