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- PDB-4i0h: SPR and structural analysis yield insight towards mechanism of in... -

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Basic information

Entry
Database: PDB / ID: 4i0h
TitleSPR and structural analysis yield insight towards mechanism of inhibition of BACE inhibitors.
ComponentsBeta-secretase 1
Keywordshydrolase/hydrolase inhibitor / BACE / Asp protease / hydrolysis / 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 / 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-1BL / 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 1.0Mar 6, 2013Provider: repository / Type: Initial release

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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)138,0176
Polymers136,3353
Non-polymers1,6823
Water5,386299
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,0062
Polymers45,4451
Non-polymers5611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,0062
Polymers45,4451
Non-polymers5611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,0062
Polymers45,4451
Non-polymers5611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)83.201, 105.467, 100.265
Angle α, β, γ (deg.)90.00, 105.11, 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
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-1BL / (2R)-5-{[(2S,3R)-4-{[1-(3-tert-butylphenyl)cyclohexyl]amino}-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]amino}-2-hydroxy-5-oxopentanoic acid


Mass: 560.672 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C31H42F2N2O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 299 / 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: 3.12 Å3/Da / Density % sol: 60.51 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.3
Details: Human BACE protein containing residues 57-453 and a C-terminal 6His-tag was concentrated to 6mg/ml in buffer 0.1M borate pH 8.5. Compound was added to give a final molar access of compound: ...Details: Human BACE protein containing residues 57-453 and a C-terminal 6His-tag 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 was obtained by sitting-drop vapor diffusion method at 291K against a reservoir containing 0.1 M sodium acetate, 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 RAXIS HTC / Detector: IMAGE PLATE / Date: Jan 1, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→60 Å / Num. all: 84800 / Num. obs: 87435 / % possible obs: 97 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.5.0102refinement
CrystalCleardata reduction
CrystalCleardata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→60 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.933 / SU B: 7.136 / SU ML: 0.175 / Cross valid method: THROUGHOUT / ESU R: 0.226 / ESU R Free: 0.204 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2667 4201 5 %RANDOM
Rwork0.21703 ---
obs0.21961 79824 99.09 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 67.888 Å2
Baniso -1Baniso -2Baniso -3
1--0.5 Å20 Å2-1.43 Å2
2--1.5 Å20 Å2
3----1.75 Å2
Refinement stepCycle: LAST / Resolution: 2.2→60 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8833 0 120 299 9252
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0229194
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.0191.96112504
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.10751114
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.64223.72414
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.585151439
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6531551
X-RAY DIFFRACTIONr_chiral_restr0.1420.21353
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0217038
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_it1.1141.55563
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.00728991
X-RAY DIFFRACTIONr_scbond_it2.83433631
X-RAY DIFFRACTIONr_scangle_it4.4284.53513
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 POSITIONAL0.450.5
2BMEDIUM POSITIONAL0.430.5
3CMEDIUM POSITIONAL0.560.5
1AMEDIUM THERMAL1.172
2BMEDIUM THERMAL1.452
3CMEDIUM THERMAL1.382
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.45 288 -
Rwork0.422 5502 -
obs--93.73 %

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