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- PDB-4j1k: CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-ca... -

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Basic information

Entry
Database: PDB / ID: 4j1k
TitleCRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-carboxylic acid [3-((4R,5R,6S)-2-amino-5-fluoro-4-methyl-6-trifluoromethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / protease inhibitor / 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-1HG / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.18 Å
AuthorsKuglstatter, A. / Stihle, M.
CitationJournal: J.Med.Chem. / Year: 2013
Title: beta-Secretase (BACE1) Inhibitors with High In Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer s Disease
Authors: Hilpert, H. / Guba, W. / Woltering, T.J. / Wostl, W. / Pinard, E. / Mauser, H. / Mayweg, A.V. / Rogers-Evans, M. / Humm, R. / Krummenacher, D. / Muser, T. / Schnider, C. / Jacobsen, H. / ...Authors: Hilpert, H. / Guba, W. / Woltering, T.J. / Wostl, W. / Pinard, E. / Mauser, H. / Mayweg, A.V. / Rogers-Evans, M. / Humm, R. / Krummenacher, D. / Muser, T. / Schnider, C. / Jacobsen, H. / Ozmen, L. / Bergadano, A. / Banner, D.W. / Hochstrasser, R. / Kuglstatter, A. / David-Pierson, P. / Fischer, H. / Polara, A. / Narquizian, R.
History
DepositionFeb 1, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,1175
Polymers45,5541
Non-polymers5634
Water2,558142
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.873, 102.873, 169.209
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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: 45554.008 Da / Num. of mol.: 1 / Mutation: K307A
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-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-1HG / N-{3-[(4R,5R,6S)-2-amino-5-fluoro-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl]-4-fluorophenyl}-5-cyanopyridine-2-carboxamide


Mass: 439.339 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H14F5N5O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 142 / 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: 2.84 Å3/Da / Density % sol: 56.64 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 2.5M SODIUM FORMATE, 100MM HEPES, pH 7.0, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 2, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.07→49.21 Å / Num. obs: 33019 / % possible obs: 100 % / Redundancy: 19.4 % / Biso Wilson estimate: 50 Å2 / Net I/σ(I): 15.1
Reflection shellResolution: 2.07→2.18 Å / Redundancy: 19.9 % / Mean I/σ(I) obs: 1.2 / Num. unique all: 4722 / % possible all: 100

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Processing

Software
NameClassification
RemDAqdata collection
REFMACrefinement
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.18→47.66 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.945 / SU B: 11.228 / SU ML: 0.125 / Cross valid method: THROUGHOUT / ESU R: 0.191 / ESU R Free: 0.17 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.22665 1429 5 %RANDOM
Rwork0.1871 ---
obs0.18905 26885 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 45.889 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20.02 Å20 Å2
2--0.05 Å20 Å2
3----0.07 Å2
Refinement stepCycle: LAST / Resolution: 2.18→47.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2904 0 37 142 3083
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0193016
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.0371.9584099
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7415364
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.40123.623138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.2915475
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.6661518
X-RAY DIFFRACTIONr_chiral_restr0.1470.2442
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212311
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.18→2.237 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.314 101 -
Rwork0.332 1949 -
obs--99.95 %
Refinement TLS params.Method: refined / Origin x: -13.0947 Å / Origin y: -41.2534 Å / Origin z: 0.0671 Å
111213212223313233
T0.0367 Å2-0.0213 Å2-0.0164 Å2-0.0316 Å20.0072 Å2--0.0457 Å2
L3.2808 °2-1.4791 °21.1631 °2-0.862 °2-0.3393 °2--1.3446 °2
S0.0314 Å °-0.0107 Å °-0.3054 Å °-0.0067 Å °0.0276 Å °0.1751 Å °0.0476 Å °-0.0097 Å °-0.0589 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1001 - 1142
2X-RAY DIFFRACTION1A501 - 504
3X-RAY DIFFRACTION1A57 - 446

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