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- PDB-2fdp: Crystal structure of beta-secretase complexed with an amino-ethyl... -

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Basic information

Entry
Database: PDB / ID: 2fdp
TitleCrystal structure of beta-secretase complexed with an amino-ethylene inhibitor
ComponentsBeta-secretase 1
KeywordsHYDROLASE / ASPARTYL PROTEASE / BACE
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-FRP / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsYang, W. / Lu, W. / Lu, Y. / Zhong, M. / Sun, J. / Thomas, A.E. / Wilkinson, J.M. / Fucini, R.V. / Lam, M. / Randal, M. ...Yang, W. / Lu, W. / Lu, Y. / Zhong, M. / Sun, J. / Thomas, A.E. / Wilkinson, J.M. / Fucini, R.V. / Lam, M. / Randal, M. / Shi, X.P. / Jacobs, J.W. / McDowell, R.S. / Gordon, E.M. / Ballinger, M.D.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Aminoethylenes: a tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1.
Authors: Yang, W. / Lu, W. / Lu, Y. / Zhong, M. / Sun, J. / Thomas, A.E. / Wilkinson, J.M. / Fucini, R.V. / Lam, M. / Randal, M. / Shi, X.P. / Jacobs, J.W. / McDowell, R.S. / Gordon, E.M. / Ballinger, M.D.
History
DepositionDec 14, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 24, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Apr 3, 2024Group: 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)131,4496
Polymers129,7673
Non-polymers1,6823
Water1,802100
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8162
Polymers43,2561
Non-polymers5611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8162
Polymers43,2561
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)43,8162
Polymers43,2561
Non-polymers5611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.189, 102.188, 99.530
Angle α, β, γ (deg.)90.00, 103.21, 90.00
Int Tables number4
Space group name H-MP1211

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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: 43255.754 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-FRP / N1-((2S,3S,5R)-3-AMINO-6-(4-FLUOROPHENYLAMINO)-5-METHYL-6-OXO-1-PHENYLHEXAN-2-YL)-N3,N3-DIPROPYLISOPHTHALAMIDE


Mass: 560.702 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C33H41FN4O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 100 / 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: 3.1 Å3/Da / Density % sol: 60.27 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL1-5 / Wavelength: 1 Å
DetectorDetector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→19.79 Å / Num. all: 54657 / Num. obs: 54657 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Biso Wilson estimate: 55.1 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 10.2
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 3.69 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 2.5 / Num. unique all: 5423 / % possible all: 100

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Processing

Software
NameVersionClassificationNB
d*TREKdata scaling
REFMAC5.1.19refinement
PDB_EXTRACT1.7data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: previously refined model

Resolution: 2.5→20 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.907 / SU B: 11.434 / SU ML: 0.239 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.441 / ESU R Free: 0.271 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.254 2767 5.1 %RANDOM
Rwork0.225 ---
all0.227 54121 --
obs0.227 54121 98.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.082 Å2
Baniso -1Baniso -2Baniso -3
1-0.35 Å20 Å2-0.27 Å2
2---0.07 Å20 Å2
3----0.4 Å2
Refinement stepCycle: LAST / Resolution: 2.5→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8785 0 123 100 9008
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0219148
X-RAY DIFFRACTIONr_angle_refined_deg0.861.95612425
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.97851107
X-RAY DIFFRACTIONr_chiral_restr0.0540.21341
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.027054
X-RAY DIFFRACTIONr_nbd_refined0.1610.23836
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0960.2356
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1790.281
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0540.22
X-RAY DIFFRACTIONr_mcbond_it1.0662.55535
X-RAY DIFFRACTIONr_mcangle_it1.89458943
X-RAY DIFFRACTIONr_scbond_it0.9672.53613
X-RAY DIFFRACTIONr_scangle_it1.60653482
LS refinement shellResolution: 2.5→2.586 Å / Total num. of bins used: 15
RfactorNum. reflection
Rfree0.365 243
Rwork0.323 4891
all-5134

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