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- PDB-5f01: CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH (1SR,2SR)-2-((R)-2-am... -

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Basic information

Entry
Database: PDB / ID: 5f01
TitleCRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH (1SR,2SR)-2-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-N-(3-chloroquinolin-8-yl)cyclopropanecarboxamide
ComponentsBeta-secretase 1
KeywordsHYDROLASE / PROTEASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to manganese ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / recycling endosome / protein processing / response to lead ion / cellular response to amyloid-beta / synaptic vesicle / late endosome / peptidase activity / positive regulation of neuron apoptotic process / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / endosome / endosome membrane / membrane raft / endoplasmic reticulum lumen / Amyloid fiber formation / axon / neuronal cell body / dendrite / enzyme binding / cell surface / Golgi apparatus / 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-5T7 / ACETATE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.52 Å
AuthorsBanner, D. / Benz, J. / Stihle, M. / Kuglstatter, A.
CitationJournal: J.Med.Chem. / Year: 2016
Title: A Real-World Perspective on Molecular Design.
Authors: Kuhn, B. / Guba, W. / Hert, J. / Banner, D. / Bissantz, C. / Ceccarelli, S. / Haap, W. / Korner, M. / Kuglstatter, A. / Lerner, C. / Mattei, P. / Neidhart, W. / Pinard, E. / Rudolph, M.G. / ...Authors: Kuhn, B. / Guba, W. / Hert, J. / Banner, D. / Bissantz, C. / Ceccarelli, S. / Haap, W. / Korner, M. / Kuglstatter, A. / Lerner, C. / Mattei, P. / Neidhart, W. / Pinard, E. / Rudolph, M.G. / Schulz-Gasch, T. / Woltering, T. / Stahl, M.
History
DepositionNov 27, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Feb 24, 2016Provider: repository / Type: Initial release
Revision 1.1May 25, 2016Group: Database references
Revision 1.2Nov 29, 2017Group: Database references / Category: pdbx_database_related
Revision 1.3May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / pdbx_struct_special_symmetry / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id
Revision 1.4Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)44,1608
Polymers43,4121
Non-polymers7487
Water7,368409
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint-14 kcal/mol
Surface area16180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.413, 102.413, 170.162
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-134-

GLN

21A-604-

HOH

31A-694-

HOH

41A-881-

HOH

51A-976-

HOH

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Components

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Protein , 1 types, 1 molecules A

#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: 43411.895 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

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Non-polymers , 6 types, 416 molecules

#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.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-5T7 / (1~{R},2~{R})-2-[(4~{R})-2-azanyl-5,5-bis(fluoranyl)-4-methyl-6~{H}-1,3-oxazin-4-yl]-~{N}-(3-chloranylquinolin-8-yl)cyclopropane-1-carboxamide


Mass: 394.803 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17ClF2N4O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 409 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.02 Å3/Da / Density % sol: 59.23 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 2.5M SODIUM FORMATE, 100MM HEPES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 24, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.52→47.78 Å / Num. obs: 75036 / % possible obs: 100 % / Redundancy: 12.81 % / Rsym value: 0.0393 / Net I/σ(I): 14.01
Reflection shellResolution: 1.52→1.62 Å / Redundancy: 12.45 % / Rmerge(I) obs: 0.5483 / Mean I/σ(I) obs: 1.83 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.6.0077refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house structure

Resolution: 1.52→47.78 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.96 / SU B: 1.401 / SU ML: 0.05 / Cross valid method: THROUGHOUT / ESU R: 0.071 / ESU R Free: 0.07 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2061 4011 5.1 %RANDOM
Rwork0.18604 ---
obs0.18704 75036 97.15 %-
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: 26.806 Å2
Baniso -1Baniso -2Baniso -3
1--0.07 Å2-0.04 Å20 Å2
2---0.07 Å20 Å2
3---0.11 Å2
Refinement stepCycle: 1 / Resolution: 1.52→47.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3009 0 47 409 3465
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0223287
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2961.9614500
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3535425
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.39423.444151
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.4815532
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.0241523
X-RAY DIFFRACTIONr_chiral_restr0.0860.2492
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212549
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: 1.52→1.559 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.365 279 -
Rwork0.327 5096 -
obs--90.63 %

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