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- PDB-6pz4: co-crystal structure of BACE with inhibitor AM-6494 -

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Basic information

Entry
Database: PDB / ID: 6pz4
Titleco-crystal structure of BACE with inhibitor AM-6494
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / BACE / inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
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
IODIDE ION / Chem-P6J / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsHuang, X.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of AM-6494: A Potent and Orally Efficacious beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor with in Vivo Selectivity over BACE2.
Authors: Pettus, L.H. / Bourbeau, M.P. / Bradley, J. / Bartberger, M.D. / Chen, K. / Hickman, D. / Johnson, M. / Liu, Q. / Manning, J.R. / Nanez, A. / Siegmund, A.C. / Wen, P.H. / Whittington, D.A. / ...Authors: Pettus, L.H. / Bourbeau, M.P. / Bradley, J. / Bartberger, M.D. / Chen, K. / Hickman, D. / Johnson, M. / Liu, Q. / Manning, J.R. / Nanez, A. / Siegmund, A.C. / Wen, P.H. / Whittington, D.A. / Allen, J.R. / Wood, S.
History
DepositionJul 31, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 23, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,9177
Polymers45,8781
Non-polymers1,0386
Water6,630368
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Beta-secretase 1
hetero molecules

A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,83414
Polymers91,7572
Non-polymers2,07712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_555x,x-y,-z+1/61
Buried area5920 Å2
ΔGint-11 kcal/mol
Surface area28410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.186, 102.186, 171.466
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-624-

HOH

21A-702-

HOH

31A-930-

HOH

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Components

#1: Protein Beta-secretase 1 / Aspartyl protease 2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP ...Aspartyl protease 2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 45878.477 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-P6J / N-{3-[(1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl}-5-[(prop-2-yn-1-yl)oxy]pyrazine-2-carboxamide


Mass: 473.496 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21F2N5O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 368 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.05 Å3/Da / Density % sol: 59.63 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.6
Details: 21% PEG 5000 MME, 190 mM Na citrate (pH 6.6), 190 mM ammonium iodide, 3% (v/v) DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 26, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 43328 / % possible obs: 100 % / Redundancy: 11.6 % / Rmerge(I) obs: 0.129 / Net I/σ(I): 5.4
Reflection shellResolution: 1.85→1.9 Å / Rmerge(I) obs: 0.911 / Num. unique obs: 2842

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
PDB_EXTRACT3.25data extraction
DENZOdata reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→50 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.935 / SU B: 2.729 / SU ML: 0.082 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.129 / ESU R Free: 0.119
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2251 2287 5 %RANDOM
Rwork0.2023 ---
obs0.2035 43238 99.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 75.26 Å2 / Biso mean: 21.006 Å2 / Biso min: 8.64 Å2
Baniso -1Baniso -2Baniso -3
1--0.1 Å2-0.05 Å20 Å2
2---0.1 Å20 Å2
3---0.16 Å2
Refinement stepCycle: final / Resolution: 1.85→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2988 0 48 368 3404
Biso mean--24.68 32.06 -
Num. residues----380
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.023112
X-RAY DIFFRACTIONr_bond_other_d0.0010.022080
X-RAY DIFFRACTIONr_angle_refined_deg1.241.9624234
X-RAY DIFFRACTIONr_angle_other_deg0.8143.0045025
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3165378
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.69923.857140
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.02515489
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9561517
X-RAY DIFFRACTIONr_chiral_restr0.0680.2462
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213458
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02659
LS refinement shellResolution: 1.851→1.899 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.332 142 -
Rwork0.305 2842 -
all-2984 -
obs--95.34 %

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