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- PDB-4joo: Spirocyclic Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1... -

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Basic information

Entry
Database: PDB / ID: 4joo
TitleSpirocyclic Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / multivesicular body / hippocampal mossy fiber to CA3 synapse / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / 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-1M4 / 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. / Smith, D.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Spirocyclic beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: from hit to lowering of cerebrospinal fluid (CSF) amyloid beta in a higher species.
Authors: Hunt, K.W. / Cook, A.W. / Watts, R.J. / Clark, C.T. / Vigers, G. / Smith, D. / Metcalf, A.T. / Gunawardana, I.W. / Burkard, M. / Cox, A.A. / Geck Do, M.K. / Dutcher, D. / Thomas, A.A. / ...Authors: Hunt, K.W. / Cook, A.W. / Watts, R.J. / Clark, C.T. / Vigers, G. / Smith, D. / Metcalf, A.T. / Gunawardana, I.W. / Burkard, M. / Cox, A.A. / Geck Do, M.K. / Dutcher, D. / Thomas, A.A. / Rana, S. / Kallan, N.C. / DeLisle, R.K. / Rizzi, J.P. / Regal, K. / Sammond, D. / Groneberg, R. / Siu, M. / Purkey, H. / Lyssikatos, J.P. / Marlow, A. / Liu, X. / Tang, T.P.
History
DepositionMar 18, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 10, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2013Group: Database references
Revision 1.2May 25, 2016Group: Structure summary
Revision 1.3Sep 20, 2023Group: 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 / struct_conn / struct_ref_seq_dif / struct_site
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.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)45,9014
Polymers45,4451
Non-polymers4563
Water5,981332
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)91,8018
Polymers90,8902
Non-polymers9116
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_655-x+1,y,-z+1/21
Buried area2710 Å2
ΔGint-39 kcal/mol
Surface area33440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.400, 103.940, 99.620
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-891-

HOH

21A-895-

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: Bace1 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-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ni
#3: Chemical ChemComp-1M4 / (4R)-2'-amino-6-bromo-1',2,2-trimethyl-2,3-dihydrospiro[chromene-4,4'-imidazol]-5'(1'H)-one


Mass: 338.200 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H16BrN3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 332 / 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: 2.15 Å3/Da / Density % sol: 42.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 16% PEG3K, 0.1M NaAcetate, 5% DMSO , pH 4.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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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: Jan 16, 2012
RadiationProtocol: 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: 36596 / Num. obs: 35953 / % possible obs: 98.2 % / Observed criterion σ(F): 2 / Redundancy: 6.63 % / Rmerge(I) obs: 0.054 / Rsym value: 0.05 / Net I/σ(I): 12.98
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 3.91 % / Rmerge(I) obs: 2 / Mean I/σ(I) obs: 9.8 / Rsym value: 0.081 / % possible all: 88.7

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.7.0029refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OAH

2oah


Resolution: 1.8→29.18 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.938 / SU B: 2.539 / SU ML: 0.081 / Cross valid method: THROUGHOUT / ESU R: 0.144 / ESU R Free: 0.129 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21806 1796 5 %RANDOM
Rwork0.18702 ---
obs0.18857 34128 98.16 %-
all-36596 --
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: 24.405 Å2
Baniso -1Baniso -2Baniso -3
1--0.42 Å20 Å2-0 Å2
2---0.65 Å2-0 Å2
3---1.07 Å2
Refinement stepCycle: LAST / Resolution: 1.8→29.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3163 0 22 332 3517
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0193271
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0971.9494456
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.035401
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.10423.882152
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.7115514
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.0331518
X-RAY DIFFRACTIONr_chiral_restr0.0730.2479
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212527
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: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.245 100 -
Rwork0.229 2138 -
obs--84.04 %

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