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- PDB-2va5: X-ray crystal structure of beta secretase complexed with compound 8c -

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Basic information

Entry
Database: PDB / ID: 2va5
TitleX-ray crystal structure of beta secretase complexed with compound 8c
ComponentsBETA-SECRETASE 1 .
KeywordsHYDROLASE / BASE / ZYMOGEN / PROTEASE / MEMBRANE / ALZHEIMER'S DISEASE / ALTERNATIVE SPLICING / MEMAPSIN 2 / GLYCOPROTEIN / TRANSMEMBRANE / BETA-SECRETASE / ASPARTYL PROTEASE / ASPARTIC PROTEASE
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 / cellular response to manganese ion / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain ...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 / cellular response to manganese ion / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to copper ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / response to lead ion / 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 / endosome membrane / 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-C8C / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsEdwards, P.D. / Albert, J.S. / Sylvester, M. / Aharony, D. / Andisik, D. / Callaghan, O. / Campbell, J.B. / Carr, R.A. / Chessari, G. / Congreve, M. ...Edwards, P.D. / Albert, J.S. / Sylvester, M. / Aharony, D. / Andisik, D. / Callaghan, O. / Campbell, J.B. / Carr, R.A. / Chessari, G. / Congreve, M. / Frederickson, M. / Folmer, R.H.A. / Geschwindner, S. / Koether, G. / Kolmodin, K. / Krumrine, J. / Mauger, R.C. / Murray, C.W. / Olsson, L. / Patel, S. / Spear, N. / Tian, G.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Application of Fragment-Based Lead Generation to the Discovery of Novel, Cyclic Amidine Beta-Secretase Inhibitors with Nanomolar Potency, Cellular Activity, and High Ligand Efficiency.
Authors: Edwards, P.D. / Albert, J.S. / Sylvester, M. / Aharony, D. / Andisik, D. / Callaghan, O. / Campbell, J.B. / Carr, R.A. / Chessari, G. / Congreve, M. / Frederickson, M. / Folmer, R.H. / ...Authors: Edwards, P.D. / Albert, J.S. / Sylvester, M. / Aharony, D. / Andisik, D. / Callaghan, O. / Campbell, J.B. / Carr, R.A. / Chessari, G. / Congreve, M. / Frederickson, M. / Folmer, R.H. / Geschwindner, S. / Koether, G. / Kolmodin, K. / Krumrine, J. / Mauger, R.C. / Murray, C.W. / Olsson, L.L. / Patel, S. / Spear, N. / Tian, G.
History
DepositionAug 30, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 13, 2007Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf
Revision 1.4Nov 6, 2024Group: Refinement description / Structure summary
Category: pdbx_entry_details / pdbx_modification_feature / software
Item: _pdbx_entry_details.has_protein_modification / _software.name
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: BETA-SECRETASE 1 .
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,7034
Polymers50,1951
Non-polymers5083
Water1,22568
1
A: BETA-SECRETASE 1 .
hetero molecules

A: BETA-SECRETASE 1 .
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,4058
Polymers100,3892
Non-polymers1,0166
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_555x,x-y,-z+1/61
Buried area3740 Å2
ΔGint-12.9 kcal/mol
Surface area36600 Å2
MethodPQS
Unit cell
Length a, b, c (Å)102.138, 102.138, 168.258
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-2053-

HOH

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Components

#1: Protein BETA-SECRETASE 1 . / BETA-SITE APP CLEAVING ENZYME 1 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / MEMBRANE- ...BETA-SITE APP CLEAVING ENZYME 1 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / MEMBRANE-ASSOCIATED ASPARTIC PROTEASE 2 / MEMAPSIN-2 / ASPARTYL PROTEASE 2 / ASP 2 / ASP2


Mass: 50194.559 Da / Num. of mol.: 1 / Fragment: PROTEASE DOMAIN, RESIDUES 14-453 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Organ: BRAIN / Plasmid: PET / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-C8C / 2-amino-6-[2-(1H-indol-6-yl)ethyl]pyrimidin-4(3H)-one


Mass: 254.287 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H14N4O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, ARG 56 TO LYS ENGINEERED RESIDUE IN CHAIN A, ARG 57 TO LYS
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: 2.96 Å3/Da / Density % sol: 58.15 % / Description: NONE
Crystal growDetails: 20-22.5% (W/V) PEG 5000 MONOMETHYLETHYL (MME), 200 MM SODIUM CITRATE (PH 6.6) AND 200 MM AMMONIUM IODIDE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX14.1 / Wavelength: 0.977
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977 Å / Relative weight: 1
ReflectionResolution: 2.75→50 Å / Num. obs: 13125 / % possible obs: 98.8 % / Observed criterion σ(I): 0 / Redundancy: 2.4 % / Rmerge(I) obs: 0.12
Reflection shellResolution: 2.75→2.82 Å / Rmerge(I) obs: 0.46 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.2.0019Grefinement
MOSFLMdata reduction
SCALAdata scaling
CSearchphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1W50

1w50


Resolution: 2.75→51.07 Å / Cor.coef. Fo:Fc: 0.91 / Cor.coef. Fo:Fc free: 0.837 / SU B: 15.737 / SU ML: 0.32 / Cross valid method: THROUGHOUT / ESU R: 1.178 / ESU R Free: 0.433 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.319 690 5 %RANDOM
Rwork0.228 ---
obs0.232 13125 97.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 38.27 Å2
Baniso -1Baniso -2Baniso -3
1-0.36 Å20.18 Å20 Å2
2--0.36 Å20 Å2
3----0.54 Å2
Refinement stepCycle: LAST / Resolution: 2.75→51.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2966 0 21 68 3055
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0223065
X-RAY DIFFRACTIONr_bond_other_d0.0020.022051
X-RAY DIFFRACTIONr_angle_refined_deg1.3911.9424169
X-RAY DIFFRACTIONr_angle_other_deg0.8722.9944969
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4725375
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.38423.857140
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.13515.031485
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2511517
X-RAY DIFFRACTIONr_chiral_restr0.0780.2451
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023432
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02652
X-RAY DIFFRACTIONr_nbd_refined0.2140.2737
X-RAY DIFFRACTIONr_nbd_other0.2020.22267
X-RAY DIFFRACTIONr_nbtor_refined0.1920.21500
X-RAY DIFFRACTIONr_nbtor_other0.0890.21612
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1880.234
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2190.218
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1930.245
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1920.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.04751870
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.07463025
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.06961195
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.0877.51144
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.75→2.82 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.476 49
Rwork0.287 948

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