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- PDB-3uqr: Crystal structure of BACE1 with its inhibitor -

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Basic information

Entry
Database: PDB / ID: 3uqr
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-15-(3-[METHYL(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-8-(2-METHYLPROPYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE / 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 / endosome membrane / lysosome / endosome / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / 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-15-(3-[METHYL(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-8-(2-METHYLPROPYL)-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: 3.056 Å
AuthorsChen, T.T. / Chen, W.Y. / Li, L. / Xu, Y.C.
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
DepositionNov 21, 2011Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Nov 21, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 16, 2013Group: Database references
Revision 1.2Sep 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_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details
Revision 1.3Nov 8, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Dec 6, 2023Group: Data collection / Derived calculations / Category: chem_comp_atom / chem_comp_bond / struct_conn
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2 / _struct_conn.pdbx_leaving_atom_flag

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


Theoretical massNumber of molelcules
Total (without water)148,0906
Polymers148,0906
Non-polymers00
Water1,49583
1
A: Beta-secretase 1
D: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-15-(3-[METHYL(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-8-(2-METHYLPROPYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE


Theoretical massNumber of molelcules
Total (without water)49,3632
Polymers49,3632
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1800 Å2
ΔGint-5 kcal/mol
Surface area15100 Å2
MethodPISA
2
B: Beta-secretase 1
E: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-15-(3-[METHYL(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-8-(2-METHYLPROPYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE


Theoretical massNumber of molelcules
Total (without water)49,3632
Polymers49,3632
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1730 Å2
ΔGint-6 kcal/mol
Surface area15060 Å2
MethodPISA
3
C: Beta-secretase 1
F: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-15-(3-[METHYL(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-8-(2-METHYLPROPYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE


Theoretical massNumber of molelcules
Total (without water)49,3632
Polymers49,3632
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1710 Å2
ΔGint-6 kcal/mol
Surface area15230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.514, 132.121, 163.393
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 48339.059 Da / Num. of mol.: 3 / Fragment: UNP residues 43-454
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-15-(3-[METHYL(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-8-(2-METHYLPROPYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE


Type: Polypeptide / Class: Enzyme inhibitor / Mass: 1024.232 Da / Num. of mol.: 3 / Source method: obtained synthetically / Details: synthetic peptide inhibitor / Source: (synth.) synthetic construct
References: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-15-(3-[METHYL(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-8-(2-METHYLPROPYL)-4,7,10,15-TETRAOXO- ...References: METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-15-(3-[METHYL(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-8-(2-METHYLPROPYL)-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.: 83 / 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: 4 Å3/Da / Density % sol: 69.26 % / Mosaicity: 0.19 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 1.0M Ammonium Sulfate, 0.1M Soldium Citrate, pH 5.0, 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
DetectorDetector: CCD / Date: Mar 21, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 3.056→74.277 Å / Num. all: 43268 / Num. obs: 43268 / % possible obs: 96.5 % / Redundancy: 6.4 % / Biso Wilson estimate: 51.41 Å2 / Rsym value: 0.094 / Net I/σ(I): 16.5
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
3.06-3.223.60.4660.3442.11858951550.2280.4660.3443.180.1
3.22-3.425.20.3490.2852.53071958720.1450.3490.2855.296
3.42-3.656.90.2440.2093.53961357380.0920.2440.2098.9100
3.65-3.957.30.1630.1425.23939453620.060.1630.14213.2100
3.95-4.327.30.110.0957.73607049630.0410.110.09518.1100
4.32-4.837.20.0770.06710.83249845090.0290.0770.06723.8100
4.83-5.587.10.0790.06810.72843240060.0290.0790.06823.8100
5.58-6.8370.0690.06122380534220.0260.0690.0625.6100
6.83-9.667.10.0450.0416.81898726890.0170.0450.0435.7100
9.66-74.2776.40.0330.02921.3988215520.0130.0330.02944.899

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
PHASERphasing
PHENIX1.7_650refinement
PDB_EXTRACT3.1data extraction
ADSCQuantumdata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2B8L

2b8l


Resolution: 3.056→66.061 Å / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8212 / SU ML: 0.36 / σ(F): 0 / Phase error: 24.17 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2418 2060 5.02 %RANDOM
Rwork0.1918 ---
obs0.1943 41048 91.65 %-
all-43268 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 38.543 Å2 / ksol: 0.328 e/Å3
Displacement parametersBiso max: 141.03 Å2 / Biso mean: 57.3276 Å2 / Biso min: 19.53 Å2
Baniso -1Baniso -2Baniso -3
1-46.1344 Å2-0 Å2-0 Å2
2---19.6634 Å20 Å2
3----26.471 Å2
Refinement stepCycle: LAST / Resolution: 3.056→66.061 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8880 0 0 83 8963
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0099133
X-RAY DIFFRACTIONf_angle_d1.27812449
X-RAY DIFFRACTIONf_chiral_restr0.081362
X-RAY DIFFRACTIONf_plane_restr0.0051598
X-RAY DIFFRACTIONf_dihedral_angle_d17.6673176
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.0564-3.12750.3539810.27541837191865
3.1275-3.20570.30821090.26182002211171
3.2057-3.29240.33091190.24112239235880
3.2924-3.38920.2531230.21392489261288
3.3892-3.49860.23321360.19232569270592
3.4986-3.62370.2561400.18622641278194
3.6237-3.76870.2271320.16772682281496
3.7687-3.94020.21941390.15472700283996
3.9402-4.14790.20191630.14272755291897
4.1479-4.40780.19391490.14862743289298
4.4078-4.7480.17011460.1432803294999
4.748-5.22560.27411570.17542808296599
5.2256-5.98140.25091620.21262833299599
5.9814-7.53420.26011500.205828793029100
7.5342-66.07590.25881540.2483008316299

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