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- PDB-4pzx: Synthesis, Characterization and PK/PD Studies of a Series of Spir... -

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Basic information

Entry
Database: PDB / ID: 4pzx
TitleSynthesis, Characterization and PK/PD Studies of a Series of Spirocyclic Pyranochromene BACE1 Inhibitors
ComponentsBeta-secretase 1
Keywordshydrolase/hydrolase inhibitor / Aspartyl protease / 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-2X5 / NICKEL (II) ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsVigers, G.P.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors.
Authors: Volgraf, M. / Chan, L. / Huestis, M.P. / Purkey, H.E. / Burkard, M. / Geck Do, M. / Harris, J. / Hunt, K.W. / Liu, X. / Lyssikatos, J.P. / Rana, S. / Thomas, A.A. / Vigers, G.P. / Siu, M.
History
DepositionMar 31, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2014Group: Database references
Revision 1.2Oct 15, 2014Group: Structure summary

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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)45,8763
Polymers45,4451
Non-polymers4312
Water3,909217
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.200, 103.550, 99.510
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-744-

HOH

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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: 45445.121 Da / Num. of mol.: 1
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-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#3: Chemical ChemComp-2X5 / (4R,4a'R,10a'R)-7'-(5-chloropyridin-3-yl)-3',4',4a',10a'-tetrahydro-1'H-spiro[1,3-oxazole-4,5'-pyrano[3,4-b]chromen]-2-amine


Mass: 371.818 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18ClN3O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / 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: 2.13 Å3/Da / Density % sol: 42.29 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 16% PEG3K, 0.1M NaAcetate pH 4.5, 5% DMSO , VAPOR DIFFUSION, HANGING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Sep 19, 2011 / Details: Confocal mirrors
RadiationMonochromator: Confocal mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→30 Å / Num. all: 36181 / Num. obs: 32164 / % possible obs: 88.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.4 % / Rmerge(I) obs: 0.069 / Rsym value: 0.064 / Net I/σ(I): 11.2
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.156 / Mean I/σ(I) obs: 5.2 / Num. unique all: 5170 / Rsym value: 0.156 / % possible all: 52.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→29.92 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.927 / SU B: 2.607 / SU ML: 0.084 / Cross valid method: THROUGHOUT / ESU R: 0.167 / ESU R Free: 0.148 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.23257 1628 5.1 %RANDOM
Rwork0.19531 ---
obs0.19713 30510 88.41 %-
all-36181 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 32.312 Å2
Baniso -1Baniso -2Baniso -3
1-0.2 Å2-0 Å20 Å2
2---1.3 Å2-0 Å2
3---1.1 Å2
Refinement stepCycle: LAST / Resolution: 1.8→29.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3152 0 27 217 3396
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0193265
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0991.9514443
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0975398
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.94523.816152
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.08815516
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.6251519
X-RAY DIFFRACTIONr_chiral_restr0.0730.2478
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212509
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_it1.3933.0911598
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.3874.6221994
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.5493.2951665
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.99626.0765029
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.219 54 -
Rwork0.206 1171 -
obs--45.81 %

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