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- PDB-4zsr: BACE crystal structure with tricyclic aminothiazine inhibitor -

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Basic information

Entry
Database: PDB / ID: 4zsr
TitleBACE crystal structure with tricyclic aminothiazine inhibitor
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase Inhibitor / aspartyl / protease / beta-secretase / 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-4RY / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.65 Å
AuthorsTimm, D.E.
CitationJournal: Bioorg.Med.Chem. / Year: 2015
Title: Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.
Authors: Winneroski, L.L. / Schiffler, M.A. / Erickson, J.A. / May, P.C. / Monk, S.A. / Timm, D.E. / Audia, J.E. / Beck, J.P. / Boggs, L.N. / Borders, A.R. / Boyer, R.D. / Brier, R.A. / Hudziak, K.J. ...Authors: Winneroski, L.L. / Schiffler, M.A. / Erickson, J.A. / May, P.C. / Monk, S.A. / Timm, D.E. / Audia, J.E. / Beck, J.P. / Boggs, L.N. / Borders, A.R. / Boyer, R.D. / Brier, R.A. / Hudziak, K.J. / Klimkowski, V.J. / Garcia Losada, P. / Mathes, B.M. / Stout, S.L. / Watson, B.M. / Mergott, D.J.
History
DepositionMay 13, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2015Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2015Group: Database references
Revision 1.2Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_entry_details / pdbx_modification_feature / pdbx_prerelease_seq / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation

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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)98,6724
Polymers97,9402
Non-polymers7322
Water18,7901043
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,3362
Polymers48,9701
Non-polymers3661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,3362
Polymers48,9701
Non-polymers3661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.546, 89.795, 131.270
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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 / Fragment: 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-4RY / N-[(4aS,6S,8aR)-2-amino-5,6,7,8-tetrahydro-4a,8a-(methanooxymethano)-3,1-benzothiazin-6(4H)-yl]-3-chlorobenzamide


Mass: 365.878 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C17H20ClN3O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1043 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.6 Å3/Da / Density % sol: 52.77 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.4 / Details: PEG8000, sodium cacodylate, ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Feb 6, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 1.65→74.114 Å / Num. obs: 124205 / % possible obs: 99.9 % / Redundancy: 7.1 % / Net I/σ(I): 12.4

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Processing

Software
NameVersionClassification
REFMAC5.7.0017refinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementResolution: 1.65→74.114 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.951 / SU B: 1.69 / SU ML: 0.058 / Cross valid method: THROUGHOUT / ESU R: 0.087 / ESU R Free: 0.082 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.20348 1019 80 %RANDOM
Rwork0.18752 ---
obs0.18765 122241 99.93 %-
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: 15.61 Å2
Baniso -1Baniso -2Baniso -3
1--1.19 Å20 Å20 Å2
2--1.71 Å20 Å2
3----0.52 Å2
Refinement stepCycle: 1 / Resolution: 1.65→74.114 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6117 0 48 1043 7208
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0196445
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.441.9588807
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.575814
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.07823.966295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.713151031
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8021536
X-RAY DIFFRACTIONr_chiral_restr0.0930.2962
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0215006
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_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
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: 1.65→1.693 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.292 79 -
Rwork0.299 8977 -
obs--99.78 %

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