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

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Basic information

Entry
Database: PDB / ID: 2zjk
TitleCrystal structure of the human BACE1 catalytic domain in complex with 4-(4-fluoro-benzyl)-piperazine-2-carboxylic acid(3-mercapto-propyl)-amide
ComponentsBeta-secretase 1
KeywordsHYDROLASE / BACE1 / small-molecule inhibitor / Tethering / Alternative splicing / 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 / 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-F1K / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsRandal, M. / Lam, M.B. / Lu, W. / 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: 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 ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.4Oct 30, 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
B: Beta-secretase 1
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)136,6576
Polymers135,7233
Non-polymers9343
Water00
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,5522
Polymers45,2411
Non-polymers3111
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,5522
Polymers45,2411
Non-polymers3111
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,5522
Polymers45,2411
Non-polymers3111
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)233.149, 108.546, 64.091
Angle α, β, γ (deg.)90.00, 103.34, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31C

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: F1K / End label comp-ID: F1K / Refine code: 1 / Auth seq-ID: 1 - 449 / Label seq-ID: 21

Dom-IDAuth asym-IDLabel asym-ID
1AA - D
2BB - E
3CC - F

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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.: 3 / Fragment: BACE1 catalytic domain, UNP residues 43-446 / Mutation: T72C
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-F1K / (2S)-4-(4-fluorobenzyl)-N-(3-sulfanylpropyl)piperazine-2-carboxamide / 4-(4-fluoro-benzyl)-piperazine-2-carboxylic acid(3-mercapto-propyl)-amide


Mass: 311.418 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C15H22FN3OS
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: 2.91 Å3/Da / Density % sol: 57.69 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1M Bis-Tris pH 5.5, 0.2M lithium sulfate monohydrate, 25% w/v polyethylene glycol 3350, 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: Feb 24, 2004
RadiationMonochromator: YALE MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.8→20 Å / Num. all: 101873 / Num. obs: 37401 / Rmerge(I) obs: 0.104
Reflection shellResolution: 2.8→2.9 Å / Rmerge(I) obs: 0.555

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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: 3→20 Å / Cor.coef. Fo:Fc: 0.912 / Cor.coef. Fo:Fc free: 0.875 / SU B: 24.187 / SU ML: 0.434 / Cross valid method: THROUGHOUT / ESU R Free: 0.505 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.29316 1471 5 %RANDOM
Rwork0.24676 ---
obs0.249 28202 95.32 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 65.905 Å2
Baniso -1Baniso -2Baniso -3
1--6.6 Å20 Å2-0.7 Å2
2---1.28 Å20 Å2
3---7.56 Å2
Refinement stepCycle: LAST / Resolution: 3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8634 0 63 0 8697
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0228934
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.9161.95212153
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9651102
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.9923.607402
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.243151351
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1621552
X-RAY DIFFRACTIONr_chiral_restr0.0610.21319
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.026899
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.170.23477
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3030.25903
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1160.2227
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1590.247
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2160.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.342.55651
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.32258870
X-RAY DIFFRACTIONr_scbond_it0.9172.53806
X-RAY DIFFRACTIONr_scangle_it1.51153283
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3→3.103 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.348 114 -
Rwork0.348 2732 -
obs--95.18 %

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