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- PDB-6bfw: BACE crystal structure with hydroxy morpholine inhibitor -

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Basic information

Entry
Database: PDB / ID: 6bfw
TitleBACE crystal structure with hydroxy morpholine inhibitor
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE Inhibitor / BACE1 / beta-secretase / inhibitor / protease / HYDROLASE / 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 / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition ...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 / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / hippocampal mossy fiber to CA3 synapse / multivesicular body / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / 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-DK7 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.84 Å
AuthorsTimm, D.E.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences.
Authors: Bueno, A.B. / Agejas, J. / Broughton, H. / Dally, R. / Durham, T.B. / Espinosa, J.F. / Gonzalez, R. / Hahn, P.J. / Marcos, A. / Rodriguez, R. / Sanz, G. / Soriano, J.F. / Timm, D. / Vidal, P. ...Authors: Bueno, A.B. / Agejas, J. / Broughton, H. / Dally, R. / Durham, T.B. / Espinosa, J.F. / Gonzalez, R. / Hahn, P.J. / Marcos, A. / Rodriguez, R. / Sanz, G. / Soriano, J.F. / Timm, D. / Vidal, P. / Yang, H.C. / McCarthy, J.R.
History
DepositionOct 27, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 15, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,0707
Polymers97,9402
Non-polymers1,1295
Water14,700816
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,5814
Polymers48,9701
Non-polymers6113
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,4893
Polymers48,9701
Non-polymers5192
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.300, 86.130, 109.420
Angle α, β, γ (deg.)90.00, 100.95, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 48970.117 Da / Num. of mol.: 2
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-DK7 / N-[(1S,2S)-1-[(3R,6R)-6-(cyclohexylmethoxy)morpholin-3-yl]-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl]acetamide


Mass: 426.497 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H32F2N2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 816 / 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: 2.56 Å3/Da / Density % sol: 52.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 17% PEG 8000, 0.2M ammonium sulfate, 0.1M sodium cacodylate, pH 7.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 0.987 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Nov 8, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.84→50 Å / Num. obs: 80447 / % possible obs: 94 % / Redundancy: 2.7 % / Biso Wilson estimate: 20.22 Å2 / Net I/σ(I): 9.1

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing
RefinementResolution: 1.84→21.59 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.925 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.128 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.135 / SU Rfree Blow DPI: 0.118 / SU Rfree Cruickshank DPI: 0.115
RfactorNum. reflection% reflectionSelection details
Rfree0.206 1003 1.25 %RANDOM
Rwork0.184 ---
obs0.184 80426 93.8 %-
Displacement parametersBiso mean: 21.31 Å2
Baniso -1Baniso -2Baniso -3
1-0.0205 Å20 Å20.1194 Å2
2--0.0681 Å20 Å2
3----0.0885 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: 1 / Resolution: 1.84→21.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6129 0 78 816 7023
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0096510HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.038885HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2226SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes155HARMONIC2
X-RAY DIFFRACTIONt_gen_planes978HARMONIC5
X-RAY DIFFRACTIONt_it6510HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.8
X-RAY DIFFRACTIONt_other_torsion15.26
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion841SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8288SEMIHARMONIC4
LS refinement shellResolution: 1.84→1.89 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 -1.38 %
Rwork0.208 5663 -
all0.209 5742 -
obs--90.75 %

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