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- PDB-4dv9: Crystal structure of BACE1 with its inhibitor -

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Basic information

Entry
Database: PDB / ID: 4dv9
TitleCrystal structure of BACE1 with its inhibitor
Components
  • Beta-secretase 1
  • METHYL (2S)-1-[(2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-AMINO-3-OXOPROPYL)-2,13-DIBENZYL-12,22-DIHYDROXY-3,5,17-TRIMETHYL-8-(2-METHYLPROPYL)-4,7,10,15,18,21-HEXAOXO-19-(PROPAN-2-YL)-3,6,9,14,17,20-HEXAAZATRICOSAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE (NON-PREFERRED NAME)
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE / 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / multivesicular body / hippocampal mossy fiber to CA3 synapse / 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 / early endosome / lysosome / 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
METHYL (2S)-1-[(2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-AMINO-3-OXOPROPYL)-2,13-DIBENZYL-12,22-DIHYDROXY-3,5,17-TRIMETHYL-8-(2-METHYLPROPYL)-4,7,10,15,18,21-HEXAOXO-19-(PROPAN-2-YL)-3,6,9,14,17,20-HEXAAZATRICOSAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE (NON-PREFERRED NAME) / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.076 Å
AuthorsXu, Y.C. / Chen, W.Y. / Li, L. / Chen, T.T.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases
Authors: Liu, Y. / Zhang, W. / Li, L. / Salvador, L.A. / Chen, T.T. / Chen, W.Y. / Felsenstein, K.M. / Ladd, T.B. / Price, A.R. / Golde, T.E. / He, J. / Xu, Y.C. / Li, Y. / Luesch, H.
History
DepositionFeb 23, 2012Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jan 16, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 15, 2021Group: Database references / Derived calculations / Source and taxonomy
Category: database_2 / pdbx_entity_src_syn ...database_2 / pdbx_entity_src_syn / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entity_src_syn.ncbi_taxonomy_id / _pdbx_entity_src_syn.organism_scientific / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_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: METHYL (2S)-1-[(2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-AMINO-3-OXOPROPYL)-2,13-DIBENZYL-12,22-DIHYDROXY-3,5,17-TRIMETHYL-8-(2-METHYLPROPYL)-4,7,10,15,18,21-HEXAOXO-19-(PROPAN-2-YL)-3,6,9,14,17,20-HEXAAZATRICOSAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE (NON-PREFERRED NAME)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,5866
Polymers49,2022
Non-polymers3844
Water4,378243
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2300 Å2
ΔGint-60 kcal/mol
Surface area16440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.528, 128.846, 76.766
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Beta-secretase 1 / BACE1 / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 ...BACE1 / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 48222.922 Da / Num. of mol.: 1 / Fragment: UNP residues 43-454 / Mutation: K75A,E77A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Protein/peptide METHYL (2S)-1-[(2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-AMINO-3-OXOPROPYL)-2,13-DIBENZYL-12,22-DIHYDROXY-3,5,17-TRIMETHYL-8-(2-METHYLPROPYL)-4,7,10,15,18,21-HEXAOXO-19-(PROPAN-2-YL)-3,6,9,14,17,20-HEXAAZATRICOSAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE (NON-PREFERRED NAME)


Type: Polypeptide / Class: Enzyme inhibitor / Mass: 979.170 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: synthetic peptide inhibitor / Source: (synth.) synthetic construct (others)
References: METHYL (2S)-1-[(2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-AMINO-3-OXOPROPYL)-2,13-DIBENZYL-12,22-DIHYDROXY-3,5,17-TRIMETHYL-8-(2-METHYLPROPYL)-4,7,10,15,18,21-HEXAOXO-19-(PROPAN-2-YL)- ...References: METHYL (2S)-1-[(2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-AMINO-3-OXOPROPYL)-2,13-DIBENZYL-12,22-DIHYDROXY-3,5,17-TRIMETHYL-8-(2-METHYLPROPYL)-4,7,10,15,18,21-HEXAOXO-19-(PROPAN-2-YL)-3,6,9,14,17,20-HEXAAZATRICOSAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE (NON-PREFERRED NAME)
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 243 / 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: 2.71 Å3/Da / Density % sol: 54.54 % / Mosaicity: 0.26 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 1.7M Li2SO4, 100mM HEPES, 25% PEG3350, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97907 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 17, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97907 Å / Relative weight: 1
ReflectionResolution: 2.076→35.32 Å / Num. all: 31388 / Num. obs: 31388 / % possible obs: 98.1 % / Redundancy: 6.6 % / Biso Wilson estimate: 14.77 Å2 / Rsym value: 0.094 / Net I/σ(I): 16.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) allRmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.08-2.1950.3280.2812.22271345150.1430.3280.2817.597.9
2.19-2.3260.3020.262.52361839530.1210.3020.268.991
2.32-2.487.10.250.2163.12920141080.0940.250.21611100
2.48-2.687.30.1860.1594.22812638560.0690.1860.15913.6100
2.68-2.947.20.130.1116.22550235360.0490.130.11116.9100
2.94-3.2870.0940.0798.22259632240.0360.0940.07921.6100
3.28-3.796.50.0780.0649.51831728160.030.0780.06425.498.5
3.79-4.646.70.0650.05510.81623224170.0250.0650.05529.699.9
4.64-6.566.80.060.05211.31296619190.0230.060.05230100
6.56-35.326.10.0560.04812.4632110440.0230.0560.0482994.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.1 Å35.32 Å
Translation2.1 Å35.32 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
PHASER2.3.0phasing
PHENIX1.7_650refinement
PDB_EXTRACT3.1data extraction
ADSCQuantumdata collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.076→35.32 Å / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8741 / SU ML: 0.24 / σ(F): 0 / Phase error: 19.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2085 1562 5.04 %
Rwork0.1716 --
obs0.1735 30975 96.85 %
all-31388 -
Solvent computationShrinkage radii: 1.06 Å / VDW probe radii: 1.3 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 34.987 Å2 / ksol: 0.345 e/Å3
Displacement parametersBiso max: 113.19 Å2 / Biso mean: 20.4473 Å2 / Biso min: 4.3 Å2
Baniso -1Baniso -2Baniso -3
1--5.7888 Å2-0 Å20 Å2
2--8.1078 Å2-0 Å2
3----2.319 Å2
Refinement stepCycle: LAST / Resolution: 2.076→35.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3022 0 20 243 3285
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073133
X-RAY DIFFRACTIONf_angle_d1.0764265
X-RAY DIFFRACTIONf_chiral_restr0.077465
X-RAY DIFFRACTIONf_plane_restr0.004542
X-RAY DIFFRACTIONf_dihedral_angle_d14.6671101
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0757-2.14270.23781310.19712535266693
2.1427-2.21930.18251490.16662640278998
2.2193-2.30810.22211180.15142297241584
2.3081-2.41320.20231350.16032700283598
2.4132-2.54030.21641380.17112685282398
2.5403-2.69950.25581420.18312726286899
2.6995-2.90780.25411460.20132718286499
2.9078-3.20020.23491270.188327772904100
3.2002-3.66290.20561580.16572745290399
3.6629-4.61330.16951560.14192754291099
4.6133-35.32480.19971620.18272836299898

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