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- PDB-2f3f: Crystal Structure of the Bace complex with BDF488, a macrocyclic ... -

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Basic information

Entry
Database: PDB / ID: 2f3f
TitleCrystal Structure of the Bace complex with BDF488, a macrocyclic inhibitor
ComponentsBeta-secretase 1
KeywordsHYDROLASE / BETA-SECRETASE / MEMAPSIN2 / ALZHEIMER'S DISEASE / ASPARTIC PROTEASE / MACROCYCLIC PEPTIDOMIMETIC INHIBITOR
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 / amyloid-beta metabolic process / 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 / cellular response to manganese ion / amyloid-beta metabolic process / 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 / hippocampal mossy fiber to CA3 synapse / multivesicular body / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / lysosome / 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-AXF / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsRondeau, J.-M.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE).
Authors: Hanessian, S. / Yang, G. / Rondeau, J.-M. / Neumann, U. / Betschart, C. / Tintelnot-Blomley, M.
History
DepositionNov 21, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 5, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software

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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
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,8766
Polymers134,3323
Non-polymers1,5443
Water9,152508
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2922
Polymers44,7771
Non-polymers5151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2922
Polymers44,7771
Non-polymers5151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2922
Polymers44,7771
Non-polymers5151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)82.250, 103.202, 100.997
Angle α, β, γ (deg.)90.00, 103.03, 90.00
Int Tables number4
Space group name H-MP1211
DetailsTHE BIOLOGICAL ASSEMBLY IS A MONOMER

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Components

#1: Protein Beta-secretase 1 / Beta-site APP cleaving enzyme 1 / Beta-site amyloid precursor protein cleaving enzyme 1 / Aspartyl ...Beta-site APP cleaving enzyme 1 / Beta-site amyloid precursor protein cleaving enzyme 1 / Aspartyl protease 2 / Asp 2 / ASP2 / Membrane-associated aspartic protease 2 / Memapsin-2


Mass: 44777.336 Da / Num. of mol.: 3 / Fragment: CATALYTIC DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE / Plasmid: pET24 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-AXF / (2R,4S)-N-BUTYL-4-HYDROXY-2-METHYL- 4-((E)-(4AS,12R,15S,17AS)-15-METHYL -14,17-DIOXO-2,3,4,4A,6,9,11,12,13, 14,15,16,17,17A-TETRADECAHYDRO-1H-5 ,10-DITHIA-1,13,16-TRIAZA-BENZOCYCL OPENTADECEN-12-YL)-BUTYRAMIDE


Mass: 514.745 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C24H42N4O4S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 508 / 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: 3.11 Å3/Da / Density % sol: 60.42 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 1.0M ammonium sulfate, pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9784 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Dec 3, 2004
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9784 Å / Relative weight: 1
ReflectionResolution: 2.3→100 Å / Num. all: 72219 / Num. obs: 72219 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.9 % / Biso Wilson estimate: 47.8 Å2 / Rmerge(I) obs: 0.097 / Χ2: 1.166 / Net I/σ(I): 10.7
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.407 / Num. unique all: 7205 / Χ2: 0.5 / % possible all: 100

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT1.701data extraction
CNX2002phasing
CNX2005refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→63.29 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 16369373 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.22 3670 5.1 %RANDOM
Rwork0.19 ---
all0.192 72197 --
obs0.192 72197 99.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 52.696 Å2 / ksol: 0.364 e/Å3
Displacement parametersBiso mean: 50.6 Å2
Baniso -1Baniso -2Baniso -3
1--8 Å20 Å20.24 Å2
2--7.59 Å20 Å2
3---0.41 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.3 Å0.25 Å
Luzzati d res low-5 Å
Luzzati sigma a0.29 Å0.23 Å
Refinement stepCycle: LAST / Resolution: 2.3→63.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8885 0 102 508 9495
Refine LS restraints
Refine-IDTypeDev idealWeight
X-RAY DIFFRACTIONx_bond_d0.006
X-RAY DIFFRACTIONx_angle_deg1
X-RAY DIFFRACTIONx_dihedral_angle_d22.4
X-RAY DIFFRACTIONx_improper_angle_d0.63
X-RAY DIFFRACTIONx_mcbond_it3.171.5
X-RAY DIFFRACTIONx_mcangle_it4.612
X-RAY DIFFRACTIONx_scbond_it4.842
X-RAY DIFFRACTIONx_scangle_it6.412.5
LS refinement shellResolution: 2.3→2.44 Å / Rfactor Rfree error: 0.011 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.275 576 5.1 %
Rwork0.241 10821 -
obs-11397 94 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein.topprotein_rep.param
X-RAY DIFFRACTION2nvp-bdf488.prm
X-RAY DIFFRACTION3water.topwater_rep.param
X-RAY DIFFRACTION4cis_peptide.param

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