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- PDB-4i12: Design and synthesis of thiophene dihydroisoquinolins as novel BA... -

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Basic information

Entry
Database: PDB / ID: 4i12
TitleDesign and synthesis of thiophene dihydroisoquinolins as novel BACE-1 inhibitors
ComponentsBeta-secretase 1
Keywordshydrolase/hydrolase inhibitor / Aspartic 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 / cellular response to manganese ion / prepulse inhibition / amyloid-beta metabolic process ...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 / prepulse inhibition / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / multivesicular body / response to lead ion / trans-Golgi network / protein processing / recycling endosome / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / dendrite / neuronal cell body / 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-1BC / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsLougheed, J.C. / Brecht, E. / Yao, N.H.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors.
Authors: Xu, Y.Z. / Yuan, S. / Bowers, S. / Hom, R.K. / Chan, W. / Sham, H.L. / Zhu, Y.L. / Beroza, P. / Pan, H. / Brecht, E. / Yao, N. / Lougheed, J. / Yan, J. / Tam, D. / Ren, Z. / Ruslim, L. / Bova, M.P. / Artis, D.R.
History
DepositionNov 19, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2013Group: Database references
Revision 1.2Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,2087
Polymers45,4451
Non-polymers7636
Water2,900161
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Beta-secretase 1
hetero molecules

A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,41714
Polymers90,8902
Non-polymers1,52712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555-x,y,-z+1/21
Buried area2390 Å2
ΔGint-220 kcal/mol
Surface area33180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.458, 103.122, 98.835
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-628-

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 / Fragment: unp residues 57-453
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-1BC / 2-{(1S)-1-{[(1Z)-6-chloro-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]amino}-2-[2-propyl-4-(1H-pyrazol-4-yl)thiophen-3-yl]ethyl}pyrimidin-4(5H)-one


Mass: 521.077 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H29ClN6OS
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 161 / 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: 2.12 Å3/Da / Density % sol: 41.85 %
Crystal growTemperature: 277 K / pH: 5.3
Details: 9% PEG 8000, 100mM sodium acetate , 10mM ZnCl2, VAPOR DIFFUSION, SITTING DROP, temperature 277K, pH 5.3

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Oct 24, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.78→51.85 Å / Num. obs: 35673 / % possible obs: 95.7 %
Reflection shellResolution: 1.78→1.84 Å / % possible all: 96.7

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Processing

Software
NameClassification
CrystalCleardata collection
REFMACrefinement
CrystalCleardata reduction
CrystalCleardata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.78→51.85 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.937 / SU B: 4.022 / SU ML: 0.123 / Cross valid method: THROUGHOUT / ESU R: 0.162 / ESU R Free: 0.159 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.283 1769 5 %RANDOM
Rwork0.228 ---
obs0.231 35651 95.7 %-
all-35651 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.25 Å2
Baniso -1Baniso -2Baniso -3
1--1.12 Å20 Å20 Å2
2---1.85 Å20 Å2
3---2.96 Å2
Refinement stepCycle: LAST / Resolution: 1.78→51.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2955 0 41 161 3157
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.023073
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.111.9574179
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6225370
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.90823.643140
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.10815486
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.7111518
X-RAY DIFFRACTIONr_chiral_restr0.2010.2450
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0212358
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: 1.78→1.83 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.507 128 -
Rwork0.458 2380 -
obs--96.24 %

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