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Basic information

Entry
Database: PDB / ID: 4i0i
TitleSPR and structural analysis yield insight towards mechanism of inhibition of BACE inhibitors
ComponentsBeta-secretase 1
Keywordshydrolase/hydrolase inhibitor / BACE / Aspartic protease / hydrolysis / hydrolase-hydrolase inhibitor complex
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 membrane / endosome / 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-957 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsYao, N. / Brecht, E.
CitationJournal: To be Published
Title: SPR and structural analysis yield insight towards mechanism of inhibition of BACE inhibitors
Authors: Mondal, K. / Regnstrom, K. / Morishige, W. / Barbour, R. / Beroza, P. / Yao, N. / Bova, M.P.
History
DepositionNov 16, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 20, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / 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 / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta- ...Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 45445.121 Da / Num. of mol.: 3 / Fragment: unp residues 57-453
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


Mass: 18.015 Da / Num. of mol.: 356 / 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: 3.06 Å3/Da / Density % sol: 59.75 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.3
Details: Human BACE protein was concentrated to 6mg/ml in buffer 0.1M borate pH 8.5. Compound was added to give a final molar access of compound:protein of 8:1. Protein and compound were then ...Details: Human BACE protein was concentrated to 6mg/ml in buffer 0.1M borate pH 8.5. Compound was added to give a final molar access of compound:protein of 8:1. Protein and compound were then incubated on ice for 1 hour. The drops were set up with a 1:1(v/v) ratio of protein to mother liquor in a total volume of 2 ul. Diffraction quality crystals of BACE in complex with compound 19 was obtained by sitting-drop vapor diffusion method at 291K against a reservoir containing 0.1 M sodium acetate pH 5.3, 2% PEG8000, VAPOR DIFFUSION, SITTING DROP

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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: Jul 1, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→90 Å / Num. all: 83264 / Num. obs: 85877 / % possible obs: 97 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1

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Processing

Software
NameVersionClassification
StructureStudiodata collection
MOLREPphasing
REFMAC5.5.0102refinement
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: 0.255 / 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_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.0551.95812486
X-RAY DIFFRACTIONr_angle_other_deg
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_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_it1.1761.55568
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.12429000
X-RAY DIFFRACTIONr_scbond_it2.933610
X-RAY DIFFRACTIONr_scangle_it4.5844.53477
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

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

Dom-IDAuth asym-IDTypeRms dev position (Å)Weight position
1AMEDIUM POSITIONAL0.440.5
2BMEDIUM POSITIONAL0.460.5
3CMEDIUM POSITIONAL0.580.5
1AMEDIUM THERMAL1.252
2BMEDIUM THERMAL1.572
3CMEDIUM 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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