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- PDB-4fgx: Crystal structure of bace1 with novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 4fgx
TitleCrystal structure of bace1 with novel inhibitor
Components
  • Beta-secretase 1
  • Inhibitor (2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-amino-3-oxopropyl)-2,13-dibenzyl-12,22-dihydroxy-8-isobutyl-19-isopropyl-3,5,17-trimethyl-4,7,10,15,18,21-hexaoxo-3,6,9,14,17,20-hexaazatricosan-1-oic acid
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
DI(HYDROXYETHYL)ETHER / UREA / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.59 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. / Chen, W. / Felsenstein, K.M. / Ladd, T.B. / Price, A.R. / Golde, T.E. / He, J. / Xu, Y. / Li, Y. / Luesch, H.
History
DepositionJun 5, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 16, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 15, 2021Group: Advisory / Database references / Derived calculations
Category: database_2 / pdbx_distant_solvent_atoms ...database_2 / pdbx_distant_solvent_atoms / 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 / _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: Inhibitor (2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-amino-3-oxopropyl)-2,13-dibenzyl-12,22-dihydroxy-8-isobutyl-19-isopropyl-3,5,17-trimethyl-4,7,10,15,18,21-hexaoxo-3,6,9,14,17,20-hexaazatricosan-1-oic acid
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,5457
Polymers49,0912
Non-polymers4545
Water8,323462
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2440 Å2
ΔGint-33 kcal/mol
Surface area15850 Å2
MethodPISA
2
A: Beta-secretase 1
B: Inhibitor (2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-amino-3-oxopropyl)-2,13-dibenzyl-12,22-dihydroxy-8-isobutyl-19-isopropyl-3,5,17-trimethyl-4,7,10,15,18,21-hexaoxo-3,6,9,14,17,20-hexaazatricosan-1-oic acid
hetero molecules

A: Beta-secretase 1
B: Inhibitor (2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-amino-3-oxopropyl)-2,13-dibenzyl-12,22-dihydroxy-8-isobutyl-19-isopropyl-3,5,17-trimethyl-4,7,10,15,18,21-hexaoxo-3,6,9,14,17,20-hexaazatricosan-1-oic acid
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,09114
Polymers98,1824
Non-polymers90910
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555-x,y,-z+1/21
Buried area6890 Å2
ΔGint-92 kcal/mol
Surface area29700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.710, 128.730, 76.160
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-699-

HOH

21A-1019-

HOH

Detailsbiological unit is the same as asym.

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: Protein Beta-secretase 1 / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta- ...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 / Mutation: K136A, E138A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Protein/peptide Inhibitor (2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-amino-3-oxopropyl)-2,13-dibenzyl-12,22-dihydroxy-8-isobutyl-19-isopropyl-3,5,17-trimethyl-4,7,10,15,18,21-hexaoxo-3,6,9,14,17,20-hexaazatricosan-1-oic acid


Mass: 868.028 Da / Num. of mol.: 1 / Source method: obtained synthetically

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Non-polymers , 4 types, 467 molecules

#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-URE / UREA


Mass: 60.055 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CH4N2O
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 462 / 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: 2.66 Å3/Da / Density % sol: 53.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 1.7 M Li2SO4/100 mM 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 315r / Detector: CCD / Date: May 12, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 1.5→43.144 Å / Num. obs: 68706 / % possible obs: 99 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 22.288 Å2 / Rmerge(I) obs: 0.064 / Net I/σ(I): 17.01
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique obs% possible all
1.5-1.590.5822.95725911291398
1.59-1.70.3794.447074612381100
1.7-1.840.2356.99660271151099.9
1.84-2.010.13111.81612921064699.8
2.01-2.250.07919.0955522961999.6
2.25-2.60.05825.6949010848299.3
2.6-3.180.04134.4941205718798.8
3.18-4.480.02849.1331866556297.6
4.480.02652.7417312307793.6

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIX1.7_650refinement
PDB_EXTRACT3.11data extraction
ADSCQuantumdata collection
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.59→43.144 Å / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8965 / SU ML: 0.15 / σ(F): 1.99 / Phase error: 17.16 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1813 2062 3 %3%
Rwork0.1674 ---
obs0.1678 68698 99.17 %-
all-81377 --
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 48.76 Å2 / ksol: 0.377 e/Å3
Displacement parametersBiso max: 59.31 Å2 / Biso mean: 19.2606 Å2 / Biso min: 7.49 Å2
Baniso -1Baniso -2Baniso -3
1--4.8439 Å20 Å2-0 Å2
2--6.9487 Å20 Å2
3----2.1047 Å2
Refinement stepCycle: LAST / Resolution: 1.59→43.144 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2974 0 26 462 3462
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063086
X-RAY DIFFRACTIONf_angle_d1.1184196
X-RAY DIFFRACTIONf_chiral_restr0.076458
X-RAY DIFFRACTIONf_plane_restr0.005535
X-RAY DIFFRACTIONf_dihedral_angle_d12.2261080
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 (%)
1.59-1.6270.22741370.208744154552100
1.627-1.66770.22891360.194744124548100
1.6677-1.71280.19791380.187644364574100
1.7128-1.76320.21341370.185744504587100
1.7632-1.82010.19451370.177744284565100
1.8201-1.88510.21380.168244474585100
1.8851-1.96060.19021370.16944244561100
1.9606-2.04990.23361370.159744554592100
2.0499-2.15790.17621370.163444274564100
2.1579-2.29310.17731380.158644584596100
2.2931-2.47020.18111370.16964435457299
2.4702-2.71870.18811390.17584470460999
2.7187-3.1120.18681370.17744448458599
3.112-3.92040.15331380.15284457459598
3.9204-43.15990.15811390.15794474461395

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