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

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Basic information

Entry
Database: PDB / ID: 2zjj
TitleCrystal structure of the human BACE1 catalytic domain in complex with 4-(4-fluoro-benzyl)-piperazine-2-carboxylic acid (2-mercapto-ethyl)-amide
ComponentsBeta-secretase 1
KeywordsHYDROLASE / BACE1 / small-molecule inhibitor / Tethering / Aspartyl protease / Glycoprotein / Membrane / Protease / Transmembrane / Zymogen
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-F1J / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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

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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)45,4222
Polymers45,1251
Non-polymers2971
Water3,045169
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.210, 93.289, 100.329
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 / 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: 45124.789 Da / Num. of mol.: 1 / Fragment: BACE1 catalytic domain, UNP residues 43-446 / Mutation: K75A, E77A, T231C
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-F1J / (2S)-4-(4-fluorobenzyl)-N-(2-sulfanylethyl)piperazine-2-carboxamide / 4-(4-fluoro-benzyl)-piperazine-2-carboxylic acid(2-mercapto-ethyl)-amide


Mass: 297.392 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20FN3OS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 169 / 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: 2.45 Å3/Da / Density % sol: 49.75 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1M imidazole pH 8.0, 0.2M Ca(OAC)2, 10% PEG 8000, VAPOR DIFFUSION, SITTING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 180 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 4, 2004
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.2→20 Å / Num. obs: 18114

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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: 2.2→20 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.906 / SU B: 7.696 / SU ML: 0.194 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.548 / ESU R Free: 0.298 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26859 877 5.3 %RANDOM
Rwork0.22889 ---
obs0.231 15750 71.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.255 Å2
Baniso -1Baniso -2Baniso -3
1--3.48 Å20 Å20 Å2
2--0.47 Å20 Å2
3---3.01 Å2
Refinement stepCycle: LAST / Resolution: 2.2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2903 0 20 169 3092
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0223002
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.8731.9524079
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8015367
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.68923.723137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.41815467
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8591517
X-RAY DIFFRACTIONr_chiral_restr0.0560.2441
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.022310
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.150.21318
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3010.22005
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0810.2195
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1020.238
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.130.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0292.51880
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.7552958
X-RAY DIFFRACTIONr_scbond_it0.8152.51298
X-RAY DIFFRACTIONr_scangle_it1.31251121
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.276 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.396 56 -
Rwork0.313 1030 -
obs--48.94 %
Refinement TLS params.Method: refined / Origin x: 13.672 Å / Origin y: 37.891 Å / Origin z: 25.471 Å
111213212223313233
T0.0213 Å20.0103 Å20.0261 Å2-0.0683 Å20.0146 Å2--0.0667 Å2
L0.1357 °20.3568 °2-0.3468 °2-1.2643 °2-1.098 °2--0.9592 °2
S0.0611 Å °0.0435 Å °0.0755 Å °0.0134 Å °0.0326 Å °0.0588 Å °-0.0462 Å °-0.067 Å °-0.0937 Å °

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