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- PDB-5kr8: (4~{S},6~{S})-4-[2,4-bis(fluoranyl)phenyl]-6-(3,5-dimethyl-1,2-ox... -

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Basic information

Entry
Database: PDB / ID: 5kr8
Title(4~{S},6~{S})-4-[2,4-bis(fluoranyl)phenyl]-6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine (compound 5) bound to BACE1
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / BACE-1 / small molecule 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 / 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 / protein serine/threonine kinase binding / 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 / aspartic-type endopeptidase activity / lysosome / 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-6WE / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.118 Å
AuthorsLewis, H.A. / Wu, Y.J. / Rajamani, R. / Thompson, L.A.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine beta-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors.
Authors: Wu, Y.J. / Guernon, J. / Shi, J. / Marcin, L. / Higgins, M. / Rajamani, R. / Muckelbauer, J. / Lewis, H. / Chang, C. / Camac, D. / Toyn, J.H. / Ahlijanian, M.K. / Albright, C.F. / Macor, J.E. / Thompson, L.A.
History
DepositionJul 7, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 7, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2016Group: Database references

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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)50,6853
Polymers50,2201
Non-polymers4642
Water1,910106
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area160 Å2
ΔGint-0 kcal/mol
Surface area14880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.059, 102.059, 170.843
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-705-

HOH

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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: 50220.492 Da / Num. of mol.: 1 / Fragment: UNP residues 14-454 / Mutation: UNP residues 14-454
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-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-6WE / (4~{S},6~{S})-4-[2,4-bis(fluoranyl)phenyl]-6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine


Mass: 337.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H17F2N3OS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / 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: 51.9 %
Crystal growTemperature: 295 K / Method: vapor diffusion / pH: 6.4
Details: 10% PEG5000 MME, 9% PEG8000, 0.2 M ammonium iodide, 0.2 M sodium citrate, pH 6.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9795 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 13, 2012
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.118→48.895 Å / Num. obs: 30666 / % possible obs: 100 % / Redundancy: 14.3 % / Net I/σ(I): 30.4

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementResolution: 2.118→48.895 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.9 / Phase error: 22.23
RfactorNum. reflection% reflection
Rfree0.244 1544 5.05 %
Rwork0.2127 --
obs0.2142 30598 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.118→48.895 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2707 0 24 106 2837
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062801
X-RAY DIFFRACTIONf_angle_d1.0163819
X-RAY DIFFRACTIONf_dihedral_angle_d14.445959
X-RAY DIFFRACTIONf_chiral_restr0.065425
X-RAY DIFFRACTIONf_plane_restr0.002486
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1185-2.18690.26441350.21552569X-RAY DIFFRACTION100
2.1869-2.2650.25371300.21592589X-RAY DIFFRACTION100
2.265-2.35570.25231500.22062580X-RAY DIFFRACTION100
2.3557-2.46290.27441520.2332576X-RAY DIFFRACTION100
2.4629-2.59280.26911450.23472594X-RAY DIFFRACTION100
2.5928-2.75520.28251420.24022623X-RAY DIFFRACTION100
2.7552-2.96790.22761530.23072598X-RAY DIFFRACTION100
2.9679-3.26650.23651290.21882653X-RAY DIFFRACTION100
3.2665-3.73910.25631360.20432661X-RAY DIFFRACTION100
3.7391-4.71020.19711440.1792710X-RAY DIFFRACTION100
4.7102-48.9080.26111280.22042901X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.5606-0.9173-0.96280.73210.40230.959-0.09020.0336-0.09780.0338-0.00220.00040.1746-0.0076-0.00170.1685-0.02490.02880.1632-0.02720.134817.330229.8031-2.4081
21.0381-0.5798-0.79810.58640.35971.41090.17050.10340.4825-0.12190.0343-0.4271-0.1643-0.060.51130.16060.01320.09020.1980.01730.3648.673152.78332.785
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 47P through 202 )
2X-RAY DIFFRACTION2chain 'A' and (resid 203 through 385 )

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