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- PDB-2va7: X-ray crystal structure of beta secretase complexed with compound 27 -

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Basic information

Entry
Database: PDB / ID: 2va7
TitleX-ray crystal structure of beta secretase complexed with compound 27
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 / 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-C27 / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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.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.A. / ...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.A. / 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
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)50,9275
Polymers50,1951
Non-polymers7324
Water3,657203
1
A: BETA-SECRETASE 1 .
hetero molecules

A: BETA-SECRETASE 1 .
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,85310
Polymers100,3892
Non-polymers1,4648
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_555x,x-y,-z+1/61
Buried area3760 Å2
ΔGint-12.9 kcal/mol
Surface area35580 Å2
MethodPQS
Unit cell
Length a, b, c (Å)102.687, 102.687, 168.340
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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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.: 3 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-C27 / (6R)-2-amino-6-[2-(3'-methoxybiphenyl-3-yl)ethyl]-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-one


Mass: 351.442 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H25N3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 203 / 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

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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: 3.07 Å3/Da / Density % sol: 51.78 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 0.931
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.931 Å / Relative weight: 1
ReflectionResolution: 2.2→47 Å / Num. obs: 25942 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 2.5 % / Rmerge(I) obs: 0.07
Reflection shellResolution: 2.2→2.26 Å / Rmerge(I) obs: 0.42 / % possible all: 100

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Processing

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

1w50


Resolution: 2.2→47.46 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.9 / SU B: 6.667 / SU ML: 0.17 / Cross valid method: THROUGHOUT / ESU R: 0.245 / ESU R Free: 0.219 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.28 1378 5 %RANDOM
Rwork0.223 ---
obs0.226 25942 99.9 %-
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: 33.39 Å2
Baniso -1Baniso -2Baniso -3
1--0.25 Å2-0.12 Å20 Å2
2---0.25 Å20 Å2
3---0.37 Å2
Refinement stepCycle: LAST / Resolution: 2.2→47.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2948 0 29 203 3180
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0223054
X-RAY DIFFRACTIONr_bond_other_d0.0020.022044
X-RAY DIFFRACTIONr_angle_refined_deg1.4931.9444155
X-RAY DIFFRACTIONr_angle_other_deg0.9022.994952
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9995372
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.12523.407145
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.20515.062485
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5011517
X-RAY DIFFRACTIONr_chiral_restr0.0880.2448
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023420
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02650
X-RAY DIFFRACTIONr_nbd_refined0.2020.2629
X-RAY DIFFRACTIONr_nbd_other0.2080.22228
X-RAY DIFFRACTIONr_nbtor_refined0.1890.21464
X-RAY DIFFRACTIONr_nbtor_other0.0930.21586
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2110.255
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2220.222
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2810.261
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.220.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.06951855
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.09363001
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.09461199
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.1117.51154
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: 2.2→2.26 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.35 93
Rwork0.267 1881

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