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- PDB-3rsx: Structure of Bace-1 (Beta-Secretase) in Complex with 6-(Thiophen-... -

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Basic information

Entry
Database: PDB / ID: 3rsx
TitleStructure of Bace-1 (Beta-Secretase) in Complex with 6-(Thiophen-3-yl)quinolin-2-amine
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase Inhibitor / ASPARTIC PROTEASE / ASPARTYL PROTEASE / 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 membrane / endosome / 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
IODIDE ION / 6-(thiophen-3-yl)quinolin-2-amine / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsSickmier, E.A.
CitationJournal: J.Med.Chem. / Year: 2011
Title: From Fragment Screening to In Vivo Efficacy: Optimization of a Series of 2-Aminoquinolines as Potent Inhibitors of Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1).
Authors: Cheng, Y. / Judd, T.C. / Bartberger, M.D. / Brown, J. / Chen, K. / Fremeau, R.T. / Hickman, D. / Hitchcock, S.A. / Jordan, B. / Li, V. / Lopez, P. / Louie, S.W. / Luo, Y. / Michelsen, K. / ...Authors: Cheng, Y. / Judd, T.C. / Bartberger, M.D. / Brown, J. / Chen, K. / Fremeau, R.T. / Hickman, D. / Hitchcock, S.A. / Jordan, B. / Li, V. / Lopez, P. / Louie, S.W. / Luo, Y. / Michelsen, K. / Nixey, T. / Powers, T.S. / Rattan, C. / Sickmier, E.A. / St Jean, D.J. / Wahl, R.C. / Wen, P.H. / Wood, S.
History
DepositionMay 2, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2011Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / 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

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5566
Polymers45,8221
Non-polymers7345
Water2,432135
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.992, 101.992, 170.980
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

#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: 45822.445 Da / Num. of mol.: 1 / Fragment: UNP residues 43-453 / Mutation: R14K, R15K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-RSV / 6-(thiophen-3-yl)quinolin-2-amine


Mass: 226.297 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H10N2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 135 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.8 Å3/Da / Density % sol: 56.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.6
Details: 20% (w/v) PEG 5000 monomethylethyl ether (MME), 200mM sodium citrate (pH 6.6) and 200mM sodium iodide., VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorDate: Dec 21, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.48→50 Å / Num. all: 19657 / Num. obs: 19405 / % possible obs: 98.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMAC5.5.0109refinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.48→19.91 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.904 / Occupancy max: 1 / Occupancy min: 0 / SU B: 8.192 / SU ML: 0.186 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.272 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2591 981 5.1 %RANDOM
Rwork0.2077 ---
obs0.2103 19094 99.1 %-
all-1926 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 94.78 Å2 / Biso mean: 46.5799 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20.03 Å20 Å2
2--0.06 Å20 Å2
3----0.08 Å2
Refinement stepCycle: LAST / Resolution: 2.48→19.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2957 0 20 135 3112
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0223048
X-RAY DIFFRACTIONr_angle_refined_deg1.1881.9524144
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3025372
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.94523.813139
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.68915483
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7161517
X-RAY DIFFRACTIONr_chiral_restr0.0740.2450
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212340
X-RAY DIFFRACTIONr_mcbond_it0.6191.51859
X-RAY DIFFRACTIONr_mcangle_it1.16423006
X-RAY DIFFRACTIONr_scbond_it1.31231189
X-RAY DIFFRACTIONr_scangle_it2.2894.51138
LS refinement shellResolution: 2.48→2.543 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 64 -
Rwork0.245 1270 -
all-1334 -
obs--97.73 %

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