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- PDB-2zji: Crystal structure of the human BACE1 catalytic domain in complex ... -

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Basic information

Entry
Database: PDB / ID: 2zji
TitleCrystal structure of the human BACE1 catalytic domain in complex with N-[1-(2,6-dimethoxy-benzyl)-piperidin-4-yl]-4-mercapto-butyramide
ComponentsBeta-secretase 1
KeywordsHYDROLASE / BACE1 / small-molecule inhibitor / Aspartyl protease / Glycoprotein / Membrane / Protease / Transmembrane / Zymogen
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 membrane / endosome / 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-F1I / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsRandal, M. / Lam, M.B. / Romanowski, M.J.
CitationJournal: To be Published
Title: Fragment-based discovery of novel BACE1 inhibitors using Tethering technology
Authors: Yang, W. / Fucini, R.V. / Fahr, B.T. / Randal, M. / Lind, K.E. / Lam, M.B. / Lu, W. / Lu, Y. / Cary, D.R. / Romanowski, M.J.
History
DepositionMar 7, 2008Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 20, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Nov 10, 2021Group: Database references / Derived calculations / Category: database_2 / 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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Nov 1, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)45,5932
Polymers45,2411
Non-polymers3521
Water4,179232
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)103.306, 103.306, 168.014
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Beta-secretase 1 / Beta-site APP cleaving enzyme 1 / Beta-site amyloid precursor protein cleaving enzyme 1 / Membrane- ...Beta-site APP cleaving enzyme 1 / Beta-site amyloid precursor protein cleaving enzyme 1 / Membrane-associated aspartic protease 2 / Memapsin-2 / Aspartyl protease 2 / Asp 2 / ASP2


Mass: 45240.930 Da / Num. of mol.: 1 / Fragment: BACE1 catalytic domain, UNP residues 43-446 / Mutation: T329C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1 / Plasmid: PET11A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) Star / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-F1I / N-[1-(2,6-dimethoxybenzyl)piperidin-4-yl]-4-sulfanylbutanamide / N-[1-(2,6-dimethoxy-benzyl)-piperidin-4-yl]-4-mercapto-butyramide


Mass: 352.492 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H28N2O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / 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 / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.86 Å3/Da / Density % sol: 57 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 2.0M sodium formate, VAPOR DIFFUSION, SITTING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 180 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Dec 6, 2003
RadiationMonochromator: YALE MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.3→20 Å / Num. obs: 24184 / % possible obs: 100 % / Rmerge(I) obs: 0.078
Reflection shellResolution: 2.3→2.38 Å / Rmerge(I) obs: 0.357

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
CrystalCleardata collection
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2P8H

2p8h


Resolution: 2.3→20 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.905 / SU B: 7.071 / SU ML: 0.173 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.305 / ESU R Free: 0.23 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26376 1244 5.2 %RANDOM
Rwork0.23394 ---
obs0.2355 22764 99.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.675 Å2
Baniso -1Baniso -2Baniso -3
1--0.27 Å2-0.14 Å20 Å2
2---0.27 Å20 Å2
3---0.41 Å2
Refinement stepCycle: LAST / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2892 0 24 232 3148
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0222993
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.8831.9584063
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.975367
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.41723.459133
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.73815469
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.0091518
X-RAY DIFFRACTIONr_chiral_restr0.0560.2441
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.022290
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1530.21350
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.30.21984
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0930.2248
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1230.252
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0820.213
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.1812.51870
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.04852957
X-RAY DIFFRACTIONr_scbond_it0.952.51284
X-RAY DIFFRACTIONr_scangle_it1.54251106
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.38 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.3 127 -
Rwork0.263 2148 -
obs--98.7 %
Refinement TLS params.Method: refined / Origin x: 74.1225 Å / Origin y: 32.3756 Å / Origin z: 28.2377 Å
111213212223313233
T0.0551 Å20.0065 Å20.0069 Å2-0.0479 Å20.0506 Å2--0.0535 Å2
L2.7312 °21.9106 °2-1.2231 °2-1.4121 °2-0.9097 °2--1.3814 °2
S-0.0408 Å °0.1135 Å °0.3478 Å °-0.0607 Å °0.1178 Å °0.2335 Å °0.0294 Å °-0.0978 Å °-0.077 Å °

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