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

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Basic information

Entry
Database: PDB / ID: 4dvf
TitleCrystal structure of BACE1 with its inhibitor
Components
  • Beta-secretase 1
  • METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-8-(2-METHYLPROPYL)-15-(3-[(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to manganese ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / recycling endosome / protein processing / response to lead ion / cellular response to amyloid-beta / synaptic vesicle / late endosome / peptidase activity / positive regulation of neuron apoptotic process / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / endosome / endosome membrane / membrane raft / endoplasmic reticulum lumen / Amyloid fiber formation / 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. / 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)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-8-(2-METHYLPROPYL)-15-(3-[(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.803 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
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_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
C: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-8-(2-METHYLPROPYL)-15-(3-[(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE
D: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-8-(2-METHYLPROPYL)-15-(3-[(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE


Theoretical massNumber of molelcules
Total (without water)98,4664
Polymers98,4664
Non-polymers00
Water9,584532
1
A: Beta-secretase 1
C: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-8-(2-METHYLPROPYL)-15-(3-[(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE


Theoretical massNumber of molelcules
Total (without water)49,2332
Polymers49,2332
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1740 Å2
ΔGint-6 kcal/mol
Surface area15600 Å2
MethodPISA
2
B: Beta-secretase 1
D: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-8-(2-METHYLPROPYL)-15-(3-[(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE


Theoretical massNumber of molelcules
Total (without water)49,2332
Polymers49,2332
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1780 Å2
ΔGint-5 kcal/mol
Surface area15690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.568, 85.822, 176.654
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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.: 2 / 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)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-8-(2-METHYLPROPYL)-15-(3-[(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE


Type: Polypeptide / Class: Enzyme inhibitor / Mass: 1010.206 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: synthetic peptide inhibitor / Source: (synth.) synthetic construct (others)
References: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-8-(2-METHYLPROPYL)-15-(3-[(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-4,7,10,15-TETRAOXO- ...References: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-8-(2-METHYLPROPYL)-15-(3-[(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 532 / 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: 2.34 Å3/Da / Density % sol: 47.46 %
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: 0.97915 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: 0.97915 Å / Relative weight: 1
ReflectionResolution: 1.8→35.48 Å / Num. all: 84247 / Num. obs: 76885 / Biso Wilson estimate: 23.64 Å2

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.8 Å48.94 Å
Translation1.8 Å48.94 Å

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Processing

Software
NameVersionClassificationNB
SCALAdata scaling
PHASER2.1.4phasing
PHENIX1.7_650refinement
PDB_EXTRACT3.1data extraction
ADSCQuantumdata collection
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.803→35.477 Å / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8164 / SU ML: 0.24 / σ(F): 0 / Phase error: 25.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2384 3836 4.99 %
Rwork0.2069 --
obs0.2085 76885 91.18 %
all-84247 -
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 42.13 Å2 / ksol: 0.346 e/Å3
Displacement parametersBiso max: 94.03 Å2 / Biso mean: 31.2088 Å2 / Biso min: 11.99 Å2
Baniso -1Baniso -2Baniso -3
1--2.3168 Å20 Å2-0 Å2
2--6.3537 Å20 Å2
3----4.0369 Å2
Refinement stepCycle: LAST / Resolution: 1.803→35.477 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5963 0 0 532 6495
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0076131
X-RAY DIFFRACTIONf_angle_d1.1148339
X-RAY DIFFRACTIONf_chiral_restr0.075907
X-RAY DIFFRACTIONf_plane_restr0.0041064
X-RAY DIFFRACTIONf_dihedral_angle_d15.2332165
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 27

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8031-1.82590.32071220.25522365248781
1.8259-1.84990.28531370.25192488262586
1.8499-1.87530.32991080.26512460256883
1.8753-1.90210.3496960.29471705180158
1.9021-1.93050.49051340.43752564269888
1.9305-1.96060.2326820.26751901198364
1.9606-1.99280.28231420.23762556269887
1.9928-2.02710.2831430.22892730287393
2.0271-2.0640.27461490.21592758290795
2.064-2.10370.2711510.22572730288193
2.1037-2.14660.28351450.23142796294194
2.1466-2.19330.25231250.23312796292194
2.1933-2.24430.33671130.25652395250882
2.2443-2.30040.31781490.2772518266786
2.3004-2.36260.28091410.21322800294195
2.3626-2.43210.26141780.222810298897
2.4321-2.51060.23941700.21962887305798
2.5106-2.60030.26411370.21112936307398
2.6003-2.70430.25651490.21852936308599
2.7043-2.82740.26721350.21482961309699
2.8274-2.97640.24811620.21092978314099
2.9764-3.16270.20611570.198629573114100
3.1627-3.40680.23751590.194229653124100
3.4068-3.74930.17971530.17492848300194
3.7493-4.2910.18681690.15430093178100
4.291-5.40310.16911380.155230803218100
5.4031-35.48360.22361920.21273120331298

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