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- PDB-3nsh: BACE-1 in complex with ELN475957 -

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Basic information

Entry
Database: PDB / ID: 3nsh
TitleBACE-1 in complex with ELN475957
ComponentsBeta-secretase 1
KeywordsHYDROLASE / MEMBRANE-ASSOCIATED ASPARTIC PROTEASE 2 / MEMAPSIN-2 / ASPARTYL PROTEASE 2 / ASP 2 / ASP2 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / BETA-SITE APP CLEAVING ENZYME 1
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-957 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsProbst, G.D. / Bowers, S. / Sealy, J.M. / Brecht, E. / Yao, N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: structure-activity relationship of the aryl region.
Authors: Probst, G.D. / Bowers, S. / Sealy, J.M. / Stupi, B. / Dressen, D. / Jagodzinska, B.M. / Aquino, J. / Gailunas, A. / Truong, A.P. / Tso, L. / Xu, Y.Z. / Hom, R.K. / John, V. / Tung, J.S. / ...Authors: Probst, G.D. / Bowers, S. / Sealy, J.M. / Stupi, B. / Dressen, D. / Jagodzinska, B.M. / Aquino, J. / Gailunas, A. / Truong, A.P. / Tso, L. / Xu, Y.Z. / Hom, R.K. / John, V. / Tung, J.S. / Pleiss, M.A. / Tucker, J.A. / Konradi, A.W. / Sham, H.L. / Jagodzinski, J. / Toth, G. / Brecht, E. / Yao, N. / Pan, H. / Lin, M. / Artis, D.R. / Ruslim, L. / Bova, M.P. / Sinha, S. / Yednock, T.A. / Gauby, S. / Zmolek, W. / Quinn, K.P. / Sauer, J.M.
History
DepositionJul 1, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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

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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)137,6876
Polymers136,3353
Non-polymers1,3523
Water6,413356
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,8962
Polymers45,4451
Non-polymers4511
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,8962
Polymers45,4451
Non-polymers4511
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,8962
Polymers45,4451
Non-polymers4511
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.155, 104.592, 100.155
Angle α, β, γ (deg.)90.00, 104.50, 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-957 / N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({1-[4-(2,2-dimethylpropyl)thiophen-2-yl]cyclopropyl}amino)-2-hydroxypropyl]acetamide


Mass: 450.585 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C24H32F2N2O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 356 / 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: 3.06 Å3/Da / Density % sol: 59.75 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 5.35
Details: 0.1M sodium acetate, 2% PEG8000, pH 5.35, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Feb 26, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→70 Å / Num. all: 83264 / Num. obs: 80263 / % possible obs: 96 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.5 % / Biso Wilson estimate: 49.9 Å2 / Rmerge(I) obs: 0.065
Reflection shellResolution: 2.2→2.31 Å / Rmerge(I) obs: 0.43 / Mean I/σ(I) obs: 1 / % possible all: 96

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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 / Resolution: 2.2→20 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.933 / SU B: 6.614 / SU ML: 0.165 / Cross valid method: THROUGHOUT / ESU R Free: 0.221 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27896 4012 5 %RANDOM
Rwork0.23057 ---
obs0.23298 76217 96.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 53.746 Å2
Baniso -1Baniso -2Baniso -3
1--1.28 Å20 Å2-1.04 Å2
2--1.38 Å20 Å2
3----0.63 Å2
Refinement stepCycle: LAST / Resolution: 2.2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8844 0 93 356 9293
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0229178
X-RAY DIFFRACTIONr_angle_refined_deg2.0551.95812486
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.05651115
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.64423.735415
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.873151442
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0731551
X-RAY DIFFRACTIONr_chiral_restr0.1450.21352
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0217028
X-RAY DIFFRACTIONr_mcbond_it1.1761.55568
X-RAY DIFFRACTIONr_mcangle_it2.12429000
X-RAY DIFFRACTIONr_scbond_it2.933610
X-RAY DIFFRACTIONr_scangle_it4.5844.53477
Refine LS restraints NCS

Dom-ID: 1 / Ens-ID: 1 / Number: 2870 / Refine-ID: X-RAY DIFFRACTION

Auth asym-IDTypeRms dev position (Å)Weight position
Amedium positional0.440.5
Bmedium positional0.460.5
Cmedium positional0.580.5
Amedium thermal1.252
Bmedium thermal1.572
Cmedium thermal1.452
LS refinement shellResolution: 2.2→2.256 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.393 233 -
Rwork0.352 4232 -
obs--73.18 %

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