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- PDB-2xfi: Human BACE-1 in complex with N-((1S,2R)-3-(((1S)-2-(cyclohexylami... -

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Basic information

Entry
Database: PDB / ID: 2xfi
TitleHuman BACE-1 in complex with N-((1S,2R)-3-(((1S)-2-(cyclohexylamino)- 1-methyl-2-oxoethyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-3-((methylsulfonyl)(phenyl)amino)benzamide
ComponentsBETA-SECRETASE 1
KeywordsHYDROLASE / PROTEASE / ZYMOGEN
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 / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition ...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 / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to manganese ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / recycling endosome / protein processing / response to lead ion / cellular response to amyloid-beta / synaptic vesicle / late endosome / peptidase activity / positive regulation of neuron apoptotic process / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / endosome membrane / lysosome / endosome / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / 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-XFI / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.73 Å
AuthorsClarke, B. / Cutler, L. / Demont, E. / Dingwall, C. / Dunsdon, R. / Hawkins, J. / Howes, C. / Hussain, I. / Maile, G. / Matico, R. ...Clarke, B. / Cutler, L. / Demont, E. / Dingwall, C. / Dunsdon, R. / Hawkins, J. / Howes, C. / Hussain, I. / 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.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Bace-1 Inhibitors Using Novel Edge-to-Face Interaction with Arg-296
Authors: Clarke, B. / Cutler, L. / Demont, E. / Dingwall, C. / Dunsdon, R. / Hawkins, J. / Howes, C. / Hussain, I. / Maile, G. / Matico, R. / Mosley, J. / Naylor, A. / O'Brien, A. / Redshaw, S. / ...Authors: Clarke, B. / Cutler, L. / Demont, E. / Dingwall, C. / Dunsdon, R. / Hawkins, J. / Howes, C. / Hussain, I. / 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
DepositionMay 24, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 7, 2010Provider: 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 1.4May 15, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.5Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_entry_details.has_protein_modification / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
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)44,3682
Polymers43,7611
Non-polymers6071
Water7,242402
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.334, 76.953, 104.695
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 AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / BETA-SITE APP CLEAVING ENZYME 1 / ...BACE-1 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / BETA-SITE APP CLEAVING ENZYME 1 / MEMBRANE-ASSOCIATED ASPARTIC PROTEASE 2 / MEMAPSIN-2 / ASPARTYL PROTEASE 2 / ASP2 / ASP 2


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) / Production host: CRICETULUS GRISEUS (Chinese hamster) / Tissue (production host): OVARY / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-XFI / N-((1S,2R)-3-(((1S)-2-(CYCLOHEXYLAMINO)-1-METHYL-2-OXOETHYL)AMINO)-2-HYDROXY-1-( PHENYLMETHYL)PROPYL)-3-((METHYLSULFONYL)(PHENYL)AMINO) BENZAMIDE


Mass: 606.775 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H42N4O5S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 402 / 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
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: 2.01 Å3/Da / Density % sol: 38.32 % / 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: ID14-4 / Wavelength: 0.9393
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9393 Å / Relative weight: 1
ReflectionResolution: 1.7→25 Å / Num. obs: 40540 / % possible obs: 98.7 % / Observed criterion σ(I): 0 / Redundancy: 4.7 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 23.2
Reflection shellResolution: 1.7→1.73 Å / Rmerge(I) obs: 0.18 / Mean I/σ(I) obs: 6.8 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.73→62.01 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.955 / SU B: 1.932 / SU ML: 0.064 / Cross valid method: THROUGHOUT / ESU R: 0.112 / ESU R Free: 0.104 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.19789 1628 4 %RANDOM
Rwork0.17073 ---
obs0.17182 38878 97.13 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 22.102 Å2
Baniso -1Baniso -2Baniso -3
1-0.86 Å20 Å20 Å2
2--0.37 Å20 Å2
3----1.24 Å2
Refinement stepCycle: LAST / Resolution: 1.73→62.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2934 0 43 402 3379
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0223149
X-RAY DIFFRACTIONr_bond_other_d0.0010.022068
X-RAY DIFFRACTIONr_angle_refined_deg1.2971.9614303
X-RAY DIFFRACTIONr_angle_other_deg0.83435038
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3415392
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.68323.83141
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.46115497
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3291518
X-RAY DIFFRACTIONr_chiral_restr0.0770.2463
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213605
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02660
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_it0.7421.51912
X-RAY DIFFRACTIONr_mcbond_other0.1531.5778
X-RAY DIFFRACTIONr_mcangle_it1.39323117
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.05231237
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.4924.51186
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: 1.728→1.773 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.217 95 -
Rwork0.188 2258 -
obs--77.84 %

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