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- PDB-2vnm: Human BACE-1 in complex with 3-(1,1-dioxidotetrahydro-2H-1,2-thia... -

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Basic information

Entry
Database: PDB / ID: 2vnm
TitleHuman BACE-1 in complex with 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin- 2-yl)-5-(ethylamino)-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((3-(trifluoromethyl)phenyl)methyl)amino)propyl)benzamide
ComponentsBETA-SECRETASE 1
KeywordsHYDROLASE / ALTERNATIVE SPLICING / BETA-SITE APP CLEAVING ENZYME / BETA-SECRETASE / ASPARTYL PROTEASE / ASP-2 / BACE-1 / ZYMOGEN / PROTEASE / MEMBRANE / MEMAPSIN-2 / GLYCOPROTEIN / TRANSMEMBRANE
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 / prepulse inhibition / amyloid-beta metabolic process ...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 / prepulse inhibition / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / multivesicular body / response to lead ion / trans-Golgi network / protein processing / recycling endosome / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / dendrite / neuronal cell body / 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-CM8 / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.79 Å
AuthorsCharrier, N. / Clarke, B. / Cutler, L. / Demont, E. / Dingwall, C. / Dunsdon, R. / East, P. / Hawkins, J. / Howes, C. / Hussain, I. ...Charrier, N. / Clarke, B. / Cutler, L. / Demont, E. / Dingwall, C. / Dunsdon, R. / East, P. / Hawkins, J. / Howes, C. / Hussain, I. / Jeffrey, P. / Maile, G. / Matico, R. / Mosley, J. / Naylor, A. / OBrien, A. / Redshaw, S. / Rowland, P. / Soleil, V. / Smith, K.J. / Sweitzer, S. / Theobald, P. / Vesey, D. / Walter, D.S. / Wayne, G.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Second Generation of Hydroxyethylamine Bace-1 Inhibitors: Optimizing Potency and Oral Bioavailability.
Authors: Charrier, N. / Clarke, B. / Cutler, L. / Demont, E. / Dingwall, C. / Dunsdon, R. / East, P. / Hawkins, J. / Howes, C. / Hussain, I. / Jeffrey, P. / Maile, G. / Matico, R. / Mosley, J. / ...Authors: Charrier, N. / Clarke, B. / Cutler, L. / Demont, E. / Dingwall, C. / Dunsdon, R. / East, P. / Hawkins, J. / Howes, C. / Hussain, I. / Jeffrey, P. / Maile, G. / Matico, R. / Mosley, J. / Naylor, A. / O'Brien, A. / Redshaw, S. / Rowland, P. / Soleil, V. / Smith, K.J. / Sweitzer, S. / Theobald, P. / Vesey, D. / Walter, D.S. / Wayne, G.
History
DepositionFeb 5, 2008Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 20, 2008Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Mar 6, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.4Apr 3, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.5May 15, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
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)44,9993
Polymers43,7611
Non-polymers1,2372
Water6,593366
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)47.952, 76.217, 104.492
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 / / BACE-1 / BETA-SITE APP CLEAVING ENZYME 1 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / ...BACE-1 / 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: 43761.312 Da / Num. of mol.: 1 / Fragment: RESIDUES 61-452 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): CHO / Production host: CRICETULUS GRISEUS (Chinese hamster) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-CM8 / N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-3-(1,1-dioxido-1,2-thiazinan-2-yl)-5-(ethylamino)benzamide


Mass: 618.710 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H37F3N4O4S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 366 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, ASN 153 TO GLN ENGINEERED RESIDUE IN CHAIN A, ASN 172 TO GLN ...ENGINEERED RESIDUE IN CHAIN A, ASN 153 TO GLN ENGINEERED RESIDUE IN CHAIN A, ASN 172 TO GLN ENGINEERED RESIDUE IN CHAIN A, ASN 223 TO GLN ENGINEERED RESIDUE IN CHAIN A, ASN 354 TO GLN

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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: 1.98 Å3/Da / Density % sol: 43.59 % / Description: NONE
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: CRYSTALS GROWN BY VAPOUR DIFFUSION AT 20C USING STREAK SEEDING, WITH 10% PEG8000 AND 0.1M GLYCINE PH 3.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723
DetectorType: ADSC CCD / Detector: CCD / Date: Oct 3, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 1.79→40 Å / Num. obs: 201388 / % possible obs: 99.1 % / Observed criterion σ(I): 0 / Redundancy: 5.5 % / Biso Wilson estimate: 18.6 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 19.7
Reflection shellResolution: 1.79→1.82 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 2.9 / % possible all: 99.7

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Processing

Software
NameVersionClassification
REFMAC5.3.0006refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.79→61.55 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.932 / SU B: 2.623 / SU ML: 0.084 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.138 / ESU R Free: 0.131 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. TWO MOLECULES OF THE LIGAND SEEN IN THIS STRUCTURE, ONE IN THE ACTIVE SITE AND ONE BETWEEN CRYSTAL CONTACTS.
RfactorNum. reflection% reflectionSelection details
Rfree0.231 1469 4 %RANDOM
Rwork0.191 ---
obs0.192 35018 99.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.71 Å2
Baniso -1Baniso -2Baniso -3
1-1.43 Å20 Å20 Å2
2---0.2 Å20 Å2
3----1.23 Å2
Refinement stepCycle: LAST / Resolution: 1.79→61.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2943 0 86 366 3395
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0223121
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3611.9614259
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr
X-RAY DIFFRACTIONr_gen_planes_refined
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9341.51944
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.47923082
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.2131363
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.4354.51177
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: 1.79→1.84 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.303 81
Rwork0.252 2585

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