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- PDB-3uqp: Crystal structure of Bace1 with its inhibitor -

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Basic information

Entry
Database: PDB / ID: 3uqp
TitleCrystal structure of Bace1 with its inhibitor
Components
  • Beta-secretase 1
  • METHYL (2R)-1-[(6S,9S,12S,13S,17S,20S,23R)-9-(3-AMINO-3-OXOPROPYL)-12,23-DIBENZYL-13-HYDROXY-2,2,8,20,22-PENTAMETHYL-17-(2-METHYLPROPYL)-4,7,10,15,18,21,24-HEPTAOXO-6-(PROPAN-2-YL)-3-OXA-5,8,11,16,19,22-HEXAAZATETRACOSAN-24-YL]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 / 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 (2R)-1-[(6S,9S,12S,13S,17S,20S,23R)-9-(3-AMINO-3-OXOPROPYL)-12,23-DIBENZYL-13-HYDROXY-2,2,8,20,22-PENTAMETHYL-17-(2-METHYLPROPYL)-4,7,10,15,18,21,24-HEPTAOXO-6-(PROPAN-2-YL)-3-OXA-5,8,11,16,19,22-HEXAAZATETRACOSAN-24-YL]PYRROLIDINE-2-CARBOXYLATE / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.77 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 / 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
Revision 1.3Nov 1, 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

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
B: METHYL (2R)-1-[(6S,9S,12S,13S,17S,20S,23R)-9-(3-AMINO-3-OXOPROPYL)-12,23-DIBENZYL-13-HYDROXY-2,2,8,20,22-PENTAMETHYL-17-(2-METHYLPROPYL)-4,7,10,15,18,21,24-HEPTAOXO-6-(PROPAN-2-YL)-3-OXA-5,8,11,16,19,22-HEXAAZATETRACOSAN-24-YL]PYRROLIDINE-2-CARBOXYLATE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,4224
Polymers49,2302
Non-polymers1922
Water6,341352
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2230 Å2
ΔGint-28 kcal/mol
Surface area15590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.390, 128.060, 76.170
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-671-

HOH

21A-754-

HOH

31A-815-

HOH

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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: 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 (2R)-1-[(6S,9S,12S,13S,17S,20S,23R)-9-(3-AMINO-3-OXOPROPYL)-12,23-DIBENZYL-13-HYDROXY-2,2,8,20,22-PENTAMETHYL-17-(2-METHYLPROPYL)-4,7,10,15,18,21,24-HEPTAOXO-6-(PROPAN-2-YL)-3-OXA-5,8,11,16,19,22-HEXAAZATETRACOSAN-24-YL]PYRROLIDINE-2-CARBOXYLATE


Type: Polypeptide / Class: Enzyme inhibitor / Mass: 1007.223 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: synthetic peptide inhibitor / Source: (synth.) synthetic construct (others)
References: METHYL (2R)-1-[(6S,9S,12S,13S,17S,20S,23R)-9-(3-AMINO-3-OXOPROPYL)-12,23-DIBENZYL-13-HYDROXY-2,2,8,20,22-PENTAMETHYL-17-(2-METHYLPROPYL)-4,7,10,15,18,21,24-HEPTAOXO-6-(PROPAN-2-YL)-3-OXA- ...References: METHYL (2R)-1-[(6S,9S,12S,13S,17S,20S,23R)-9-(3-AMINO-3-OXOPROPYL)-12,23-DIBENZYL-13-HYDROXY-2,2,8,20,22-PENTAMETHYL-17-(2-METHYLPROPYL)-4,7,10,15,18,21,24-HEPTAOXO-6-(PROPAN-2-YL)-3-OXA-5,8,11,16,19,22-HEXAAZATETRACOSAN-24-YL]PYRROLIDINE-2-CARBOXYLATE
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 352 / 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: 2.63 Å3/Da / Density % sol: 53.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 1.7M Li2SO4, 100mM HEPES, 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: Jul 21, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 1.77→40.456 Å / Num. all: 43837 / Num. obs: 43705 / % possible obs: 87.4 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 15.47 Å2 / Rmerge(I) obs: 0.081 / Net I/σ(I): 13.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
1.77-1.820.6170.4952.8215669366533700.55392
1.82-1.870.4730.3843.5315381357032790.42891.8
1.87-1.920.4020.3294.2114758346231640.36791.4
1.92-1.980.30.2565.3914469337030580.28590.7
1.98-2.040.2380.26.8514123327629600.22290.4
2.04-2.120.1930.1728.0713646318928600.19189.7
2.12-2.20.160.1479.512989303226930.16388.8
2.2-2.290.1310.12610.9412584295026050.1488.3
2.29-2.390.1220.11611.9412193284824930.12887.5
2.39-2.50.1070.10612.8911591270423610.11787.3
2.5-2.640.090.09514.4911059257722260.10586.4
2.64-2.80.0810.08416.4910423245520920.09285.2
2.8-2.990.0620.07219.559696228319300.07984.5
2.99-3.230.0460.05823.729069216018160.06384.1
3.23-3.540.0350.04928.048112198516260.05481.9
3.54-3.960.0280.04131.417265181314780.04681.5
3.96-4.570.0220.03635.866759160712950.0480.6
4.57-5.60.0210.03535.535789137710960.03879.6
5.6-7.920.0220.03434.84445010768400.03878.1
7.920.0170.0340.3824266334630.03373.1

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Processing

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

2b8l


Resolution: 1.77→40.456 Å / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8954 / SU ML: 0.16 / σ(F): 2 / Phase error: 17.59 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1891 1312 3 %random
Rwork0.1652 ---
obs0.1659 43704 87.36 %-
all-43837 --
Solvent computationShrinkage radii: 0.95 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 43.002 Å2 / ksol: 0.391 e/Å3
Displacement parametersBiso max: 80.52 Å2 / Biso mean: 20.8433 Å2 / Biso min: 6.39 Å2
Baniso -1Baniso -2Baniso -3
1--5.2029 Å2-0 Å2-0 Å2
2--6.6785 Å2-0 Å2
3----1.4756 Å2
Refinement stepCycle: LAST / Resolution: 1.77→40.456 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3009 0 10 352 3371
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073116
X-RAY DIFFRACTIONf_angle_d1.1144238
X-RAY DIFFRACTIONf_chiral_restr0.076456
X-RAY DIFFRACTIONf_plane_restr0.004542
X-RAY DIFFRACTIONf_dihedral_angle_d14.0811113
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.77-1.84090.27461520.22384910506292
1.8409-1.92470.24461510.19384877502892
1.9247-2.02610.20181490.16924807495690
2.0261-2.15310.20131480.16154787493590
2.1531-2.31930.18461470.15724748489589
2.3193-2.55270.18361450.1584684482987
2.5527-2.9220.17831420.16974601474385
2.922-3.6810.17151400.15384521466183
3.681-40.4670.17221380.15814457459579

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