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- PDB-6bfx: BACE crystal structure with hydroxy pyrrolidine inhibitor -

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Basic information

Entry
Database: PDB / ID: 6bfx
TitleBACE crystal structure with hydroxy pyrrolidine inhibitor
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE Inhibitor / BACE1 / beta-secretase / inhibitor / protease / HYDROLASE / 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 / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition ...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 / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / 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 / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / 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-DKJ / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.99 Å
AuthorsTimm, D.E.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences.
Authors: Bueno, A.B. / Agejas, J. / Broughton, H. / Dally, R. / Durham, T.B. / Espinosa, J.F. / Gonzalez, R. / Hahn, P.J. / Marcos, A. / Rodriguez, R. / Sanz, G. / Soriano, J.F. / Timm, D. / Vidal, P. ...Authors: Bueno, A.B. / Agejas, J. / Broughton, H. / Dally, R. / Durham, T.B. / Espinosa, J.F. / Gonzalez, R. / Hahn, P.J. / Marcos, A. / Rodriguez, R. / Sanz, G. / Soriano, J.F. / Timm, D. / Vidal, P. / Yang, H.C. / McCarthy, J.R.
History
DepositionOct 27, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 15, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,9536
Polymers97,9402
Non-polymers1,0134
Water13,637757
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,5694
Polymers48,9701
Non-polymers5993
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,3852
Polymers48,9701
Non-polymers4141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.253, 91.321, 131.570
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 48970.117 Da / Num. of mol.: 2
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-DKJ / N-{(1S,2S)-3-(3,5-difluorophenyl)-1-[(3R,5S,6R)-6-(2,2-dimethylpropoxy)-5-methylmorpholin-3-yl]-1-hydroxypropan-2-yl}acetamide


Mass: 414.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H32F2N2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 757 / 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: 2.65 Å3/Da / Density % sol: 53.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 17% PEG 8000, 0.2M ammonium sulfate, 0.1M sodium cacodylate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Feb 3, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 1.78→25.5 Å / Num. obs: 90639 / % possible obs: 92.7 % / Redundancy: 7.4 % / Biso Wilson estimate: 25.23 Å2 / Net I/σ(I): 4.4

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
MOSFLMdata reduction
SCALAdata scaling
CNXphasing
RefinementResolution: 1.99→25.29 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.923 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.167 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.18 / SU Rfree Blow DPI: 0.156 / SU Rfree Cruickshank DPI: 0.151
RfactorNum. reflection% reflectionSelection details
Rfree0.233 984 1.45 %RANDOM
Rwork0.198 ---
obs0.198 67915 94.5 %-
Displacement parametersBiso mean: 25.95 Å2
Baniso -1Baniso -2Baniso -3
1-0.6935 Å20 Å20 Å2
2---0.998 Å20 Å2
3---0.3046 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: 1 / Resolution: 1.99→25.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6102 0 70 757 6929
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0096430HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.048816HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2159SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes152HARMONIC2
X-RAY DIFFRACTIONt_gen_planes951HARMONIC5
X-RAY DIFFRACTIONt_it6430HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.6
X-RAY DIFFRACTIONt_other_torsion15.82
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion817SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7498SEMIHARMONIC4
LS refinement shellResolution: 1.99→2.04 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.258 -1.47 %
Rwork0.195 4833 -
all0.196 4905 -
obs--93.72 %

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