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- PDB-3ixj: Crystal structure of beta-secretase 1 in complex with selective b... -

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Basic information

Entry
Database: PDB / ID: 3ixj
TitleCrystal structure of beta-secretase 1 in complex with selective beta-secretase 1 inhibitor
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / BACE / BETA SECRETASE-1 / INHIBITOR / ALTERNATIVE SPLICING / ASPARTYL PROTEASE / GLYCOPROTEIN / HYDROLASE / MEMBRANE / PROTEASE / TRANSMEMBRANE / ZYMOGEN / Disulfide bond / Polymorphism / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion ...memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / protein serine/threonine kinase binding / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / multivesicular body / hippocampal mossy fiber to CA3 synapse / response to lead ion / trans-Golgi network / recycling endosome / protein processing / positive regulation of neuron apoptotic process / cellular response to amyloid-beta / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / axon / neuronal cell body / dendrite / Golgi apparatus / enzyme binding / cell surface / 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
Chem-586 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsBorkakoti, N. / Lindberg, J. / Nystrom, S.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Design and Synthesis of Potent and Selective BACE-1 Inhibitors.
Authors: Bjorklund, C. / Oscarson, S. / Benkestock, K. / Borkakoti, N. / Jansson, K. / Lindberg, J. / Vrang, L. / Hallberg, A. / Rosenquist, A. / Samuelsson, B.
History
DepositionSep 4, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,6119
Polymers129,7673
Non-polymers2,8446
Water4,342241
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,2043
Polymers43,2561
Non-polymers9482
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,2043
Polymers43,2561
Non-polymers9482
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,2043
Polymers43,2561
Non-polymers9482
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.913, 102.705, 100.417
Angle α, β, γ (deg.)90.00, 103.42, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Beta-secretase 1 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Membrane- ...Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Membrane-associated aspartic protease 2 / Memapsin-2 / Aspartyl protease 2 / Asp 2 / ASP2


Mass: 43255.754 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Plasmid: PET11A / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-586 / N-[4-(1-BENZYLCARBAMOYL-2-METHYL-PROPYLCARBAMOYL)-1-(3,5-DIFLUORO-PHENOXYMETHYL)-2-HYDROXY-4-METHOXY-BUTYL]-5-(METHANESULFONYL-METHYL-AMINO)-N'-(1-PHENYLETHYL)-ISOPHTHALAMIDE / N-{(1S,2S,4R)-5-{[(1S)-1-(benzylcarbamoyl)-2-methylpropyl]amino}-1-[(3,5-difluorophenoxy)methyl]-2-hydroxy-4-methoxy-5-oxopentyl}-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide


Mass: 851.955 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C43H51F2N5O9S
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 241 / 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: 3.17 Å3/Da / Density % sol: 61.15 %
Crystal growTemperature: 299 K / Method: vapor diffusion / pH: 5
Details: 16% PEG 8000, 0.1M CITRATE, 0.3M LITHIUM SULFATE, 0.1M SODIUM CHLORIDE, pH 5.0, VAPOR DIFFUSION, temperature 299K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.933
DetectorType: ADSC QUANTUM 210 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.2→62.994 Å / Num. obs: 82125 / % possible obs: 100 % / Redundancy: 4 % / Rmerge(I) obs: 0.099 / Rsym value: 0.099 / Net I/σ(I): 6.2
Reflection shellResolution: 2.2→2.32 Å / Redundancy: 4 % / Rmerge(I) obs: 0.31 / Mean I/σ(I) obs: 2.5 / Rsym value: 0.31 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→62.99 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.892 / SU B: 5.056 / SU ML: 0.131 / Cross valid method: THROUGHOUT / ESU R: 0.226 / ESU R Free: 0.188 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.243 4101 5 %RANDOM
Rwork0.212 ---
obs0.213 81771 99.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.74 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20 Å20.11 Å2
2--0.25 Å20 Å2
3----0.25 Å2
Refinement stepCycle: LAST / Resolution: 2.2→62.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8805 0 195 241 9241
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0229236
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1281.9712560
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.93751108
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.97123.798416
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.912151443
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4471551
X-RAY DIFFRACTIONr_chiral_restr0.0750.21354
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.027110
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1730.23829
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3040.26165
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1040.2446
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2040.271
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1670.28
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0671.55709
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.59128954
X-RAY DIFFRACTIONr_scbond_it2.16934127
X-RAY DIFFRACTIONr_scangle_it3.2494.53606
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.26 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.304 316 -
Rwork0.247 5716 -
obs--99.23 %

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