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- PDB-6uj1: BACE2 mutant in complex with a macrocyclic compound -

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Basic information

Entry
Database: PDB / ID: 6uj1
TitleBACE2 mutant in complex with a macrocyclic compound
ComponentsBeta-secretase 2
KeywordsPEPTIDE BINDING PROTEIN / aspartic protease
Function / homology
Function and homology information


memapsin 1 / negative regulation of amyloid precursor protein biosynthetic process / melanosome membrane / melanosome organization / peptide hormone processing / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / trans-Golgi network / protein processing / glucose homeostasis ...memapsin 1 / negative regulation of amyloid precursor protein biosynthetic process / melanosome membrane / melanosome organization / peptide hormone processing / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / trans-Golgi network / protein processing / glucose homeostasis / aspartic-type endopeptidase activity / endosome / Golgi apparatus / endoplasmic reticulum / proteolysis / membrane / plasma membrane
Similarity search - Function
Beta-secretase BACE2 / Beta-secretase BACE / Memapsin-like / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily
Similarity search - Domain/homology
Chem-L3M / Beta-secretase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.03 Å
AuthorsYen, Y.C. / Ghosh, A.K. / Mesecar, A.D.
Funding support United States, 1items
OrganizationGrant numberCountry
Department of Health & Human Services (HHS) United States
CitationJournal: Acs Chem Neurosci / Year: 2021
Title: A Structure-Based Discovery Platform for BACE2 and the Development of Selective BACE Inhibitors.
Authors: Yen, Y.C. / Kammeyer, A.M. / Tirlangi, J. / Ghosh, A.K. / Mesecar, A.D.
History
DepositionOct 2, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 7, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 21, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Beta-secretase 2
B: Beta-secretase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,1424
Polymers98,8842
Non-polymers1,2582
Water0
1
A: Beta-secretase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,0712
Polymers49,4421
Non-polymers6291
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,0712
Polymers49,4421
Non-polymers6291
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)123.068, 123.068, 118.055
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Space group name HallP312"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: x-y,-y,-z+2/3
#5: -x,-x+y,-z+1/3
#6: y,x,-z

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Components

#1: Protein Beta-secretase 2 / / Aspartic-like protease 56 kDa / Aspartyl protease 1 / Asp 1 / Beta-site amyloid precursor protein ...Aspartic-like protease 56 kDa / Aspartyl protease 1 / Asp 1 / Beta-site amyloid precursor protein cleaving enzyme 2 / Beta-site APP cleaving enzyme 2 / Down region aspartic protease / DRAP / Memapsin-1 / Membrane-associated aspartic protease 1 / Theta-secretase


Mass: 49441.996 Da / Num. of mol.: 2 / Mutation: E269A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE2, AEPLC, ALP56, ASP21, CDA13, UNQ418/PRO852 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: Q9Y5Z0, memapsin 1
#2: Chemical ChemComp-L3M / (3S)-3-hydroxy-N-(2-methylpropyl)-N~2~-{[(4S)-17-[(methylsulfonyl)(propyl)amino]-2-oxo-3-azatricyclo[13.3.1.1~6,10~]icosa-1(19),6(20),7,9,15,17-hexaen-4-yl]methyl}-L-norleucinamide


Mass: 628.865 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H52N4O5S / Feature type: SUBJECT OF INVESTIGATION
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: 2.61 Å3/Da / Density % sol: 52.82 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.1 M MES (pH6) 1.4 M (NH4)2SO4 6% isopropanol 4% tertbutanol

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Data collection

DiffractionMean temperature: 77 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS3 R CdTe 300K / Detector: PIXEL / Date: Apr 18, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 3→29.77 Å / Num. obs: 20418 / % possible obs: 99.94 % / Redundancy: 2 % / CC1/2: 1 / Net I/σ(I): 11.22
Reflection shellResolution: 3.03→3.14 Å / Num. unique obs: 2015 / CC1/2: 0.621

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2EWY

2ewy


Resolution: 3.03→29.77 Å / Cross valid method: FREE R-VALUE / σ(F): 41.69 / Phase error: 35.136
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2906 1016 4.98 %
Rwork0.2404 19402 -
obs0.2457 20418 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 114.69 Å2
Refinement stepCycle: LAST / Resolution: 3.03→29.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5613 0 88 0 5701
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01885839
X-RAY DIFFRACTIONf_angle_d1.56377933
X-RAY DIFFRACTIONf_chiral_restr0.076874
X-RAY DIFFRACTIONf_plane_restr0.01041005
X-RAY DIFFRACTIONf_dihedral_angle_d16.362075
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.03-3.190.35771440.3392702X-RAY DIFFRACTION94.94
3.19-3.390.39291440.3362748X-RAY DIFFRACTION95.02
3.39-3.660.30741450.30922732X-RAY DIFFRACTION94.96
3.66-4.020.3361460.26942755X-RAY DIFFRACTION94.97
4.02-4.60.2681430.2222756X-RAY DIFFRACTION95.07
4.6-5.790.27341470.22372784X-RAY DIFFRACTION94.98
5.79-28.440.29211450.21892886X-RAY DIFFRACTION94.84

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