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- PDB-3i25: Potent Beta-Secretase 1 hydroxyethylene Inhibitor -

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Basic information

Entry
Database: PDB / ID: 3i25
TitlePotent Beta-Secretase 1 hydroxyethylene Inhibitor
ComponentsBeta-secretase 1
KeywordsHYDROLASE / BACE / BETA-SECRETASE / INHIBITOR / ASPARTYL PROTEASE / PROTEASE / Alternative splicing / Disulfide bond / Glycoprotein / Membrane / Polymorphism / 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-MV7 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsLindberg, J.D. / Borkakoti, N. / Nystrom, S.
CitationJournal: Bioorg.Med.Chem. / Year: 2010
Title: Discovery of potent BACE-1 inhibitors containing a new hydroxyethylene (HE) scaffold: exploration of P1' alkoxy residues and an aminoethylene (AE) central core
Authors: Bjorklund, C. / Adolfsson, H. / Jansson, K. / Lindberg, J. / Vrang, L. / Hallberg, A. / Rosenquist, A. / Samuelsson, B.
History
DepositionJun 29, 2009Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 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
Revision 1.3Oct 9, 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)138,8766
Polymers136,1883
Non-polymers2,6883
Water3,495194
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,2922
Polymers45,3961
Non-polymers8961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,2922
Polymers45,3961
Non-polymers8961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,2922
Polymers45,3961
Non-polymers8961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.417, 102.483, 100.186
Angle α, β, γ (deg.)90.00, 103.53, 90.00
Int Tables number4
Space group name H-MP1211

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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: 45396.082 Da / Num. of mol.: 3 / Fragment: UNP RESIDUES 42-446
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Plasmid: pET-11a / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-MV7 / N-[(2S,3S,5R)-1-(3,5-difluorophenoxy)-3-hydroxy-5-(2-methoxyethoxy)-6-[[(2S)-3-methyl-1-oxo-1-(phenylmethylamino)butan-2-yl]amino]-6-oxo-hexan-2-yl]-5-(methyl-methylsulfonyl-amino)-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide / N-[(1S,2S,4R)-4-((S)-1-Benzylcarbamoyl-2-methyl-propylcarbamoyl)-1-(3,5-difluoro-phenoxymethyl)-2-hydroxy-4-(2-methoxy-ethoxy)-butyl]-5-(methanesulfonyl-methyl-amino)-N'-((R)-1-phenyl-ethyl)-isophthalamide


Mass: 896.008 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C45H55F2N5O10S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 194 / 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: 2.98 Å3/Da / Density % sol: 58.78 %
Crystal growTemperature: 299 K / Method: vapor diffusion / pH: 5
Details: 16% PEG8000, 0.1M Citrate, 0.3M Lithium sulphate, 0.1M Sodium Chloride, pH 5.0, VAPOR DIFFUSION, temperature 299K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 1 / Detector: CCD / Date: Oct 25, 2007
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.1→102.6 Å / Num. obs: 89314 / % possible obs: 95.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3 % / Biso Wilson estimate: 38 Å2 / Rmerge(I) obs: 0.055 / Net I/σ(I): 15.1 / Num. measured all: 390639
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.271 / Mean I/σ(I) obs: 4.2 / % possible all: 79.3

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Processing

Software
NameVersionClassification
DNAdata collection
AMoREphasing
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3DM6

3dm6


Resolution: 2.1→79.16 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.932 / SU B: 4.294 / SU ML: 0.117 / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R: 0.19 / ESU R Free: 0.17 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.238 4449 5 %RANDOM
Rwork0.2 ---
all0.212 ---
obs0.202 84864 95.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.954 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å20 Å20.19 Å2
2--0.19 Å20 Å2
3----0.2 Å2
Refinement stepCycle: LAST / Resolution: 2.1→79.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8820 0 189 194 9203
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0229249
X-RAY DIFFRACTIONr_angle_refined_deg1.8861.96912573
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.93451110
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.85823.813417
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.863151446
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8831551
X-RAY DIFFRACTIONr_chiral_restr0.1450.21356
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.027122
X-RAY DIFFRACTIONr_nbd_refined0.220.23957
X-RAY DIFFRACTIONr_nbtor_refined0.3170.26147
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1640.2460
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2630.273
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2570.29
X-RAY DIFFRACTIONr_mcbond_it1.2781.55709
X-RAY DIFFRACTIONr_mcangle_it2.04328970
X-RAY DIFFRACTIONr_scbond_it2.8134135
X-RAY DIFFRACTIONr_scangle_it4.244.53603
LS refinement shellResolution: 2.1→2.155 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 255 -
Rwork0.241 4852 -
obs--74.79 %

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