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- PDB-3n4l: BACE-1 in complex with ELN380842 -

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Basic information

Entry
Database: PDB / ID: 3n4l
TitleBACE-1 in complex with ELN380842
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE inhibitor / BACE / hydroxyethylamine / beta secretase / Alzheimer's disease / AD / beta-amyloid precursor protein / beta-APP / 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 / cellular response to manganese ion / prepulse inhibition / amyloid-beta metabolic process ...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 / cellular response to manganese ion / prepulse inhibition / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / multivesicular body / response to lead ion / trans-Golgi network / protein processing / recycling endosome / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / dendrite / neuronal cell body / 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-842 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsYao, N.H.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents.
Authors: Truong, A.P. / Probst, G.D. / Aquino, J. / Fang, L. / Brogley, L. / Sealy, J.M. / Hom, R.K. / Tucker, J.A. / John, V. / Tung, J.S. / Pleiss, M.A. / Konradi, A.W. / Sham, H.L. / Dappen, M.S. ...Authors: Truong, A.P. / Probst, G.D. / Aquino, J. / Fang, L. / Brogley, L. / Sealy, J.M. / Hom, R.K. / Tucker, J.A. / John, V. / Tung, J.S. / Pleiss, M.A. / Konradi, A.W. / Sham, H.L. / Dappen, M.S. / Toth, G. / Yao, N. / Brecht, E. / Pan, H. / Artis, D.R. / Ruslim, L. / Bova, M.P. / Sinha, S. / Yednock, T.A. / Zmolek, W. / Quinn, K.P. / Sauer, J.M.
History
DepositionMay 21, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 24, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 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 / 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

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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)137,7836
Polymers136,3353
Non-polymers1,4483
Water63135
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,9282
Polymers45,4451
Non-polymers4831
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,9282
Polymers45,4451
Non-polymers4831
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,9282
Polymers45,4451
Non-polymers4831
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)83.047, 105.582, 101.575
Angle α, β, γ (deg.)90.00, 104.63, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31C

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Components

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


Mass: 45445.121 Da / Num. of mol.: 3
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-842 / N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(1H-pyrazol-1-yl)phenyl]cyclohexyl}amino)propyl]acetamide


Mass: 482.565 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H32F2N4O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 35 / 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: 3.16 Å3/Da / Density % sol: 61.08 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.1M NaAcetate, 12% w/v PEG 8000, pH 5.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Oct 28, 2009 / Details: mirrors
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.7→98.28 Å / Num. obs: 46696 / % possible obs: 98.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.2 % / Rmerge(I) obs: 0.067
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 3 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 1.4 / % possible all: 98.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.5.0102refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3IVI

3ivi


Resolution: 2.7→28 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.909 / SU B: 16.118 / SU ML: 0.319 / Cross valid method: THROUGHOUT / ESU R: 0.656 / ESU R Free: 0.353 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28266 2329 5 %RANDOM
Rwork0.22279 ---
obs0.22581 43822 98.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 68.01 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å20 Å2-3.01 Å2
2--0.52 Å20 Å2
3----2.14 Å2
Refinement stepCycle: LAST / Resolution: 2.7→28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8842 0 105 35 8982
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0229188
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.7471.95912494
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.06851116
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.17623.768414
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.266151441
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.1471551
X-RAY DIFFRACTIONr_chiral_restr0.1140.21354
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0217039
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_it0.8391.55575
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.56429014
X-RAY DIFFRACTIONr_scbond_it1.69433613
X-RAY DIFFRACTIONr_scangle_it2.9074.53480
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Ens-ID: 1 / Number: 2944 / Refine-ID: X-RAY DIFFRACTION

Auth asym-IDTypeRms dev position (Å)Weight position
Amedium positional0.420.5
Bmedium positional0.410.5
Cmedium positional0.570.5
Amedium thermal0.692
Bmedium thermal0.72
Cmedium thermal0.82
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 185 -
Rwork0.398 3237 -
obs--97.94 %

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