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- EMDB-45496: 20S Proteasome core particle in complex with Ixazomib -

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Basic information

Entry
Database: EMDB / ID: EMD-45496
Title20S Proteasome core particle in complex with Ixazomib
Map dataD7 symmetry map
Sample
  • Complex: 20S Proteasome core particle in complex with Ixazomib
    • Protein or peptide: Proteasome subunit alpha
    • Protein or peptide: Proteasome subunit beta
  • Ligand: [(1~{R})-1-[2-[[2,5-bis(chloranyl)phenyl]carbonylamino]ethanoylamino]-3-methyl-butyl]boronic acid
KeywordsProteasome / Proteolysis / ANTIMICROBIAL PROTEIN
Function / homology
Function and homology information


symbiont-mediated perturbation of host defenses / zymogen binding / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / proteolysis involved in protein catabolic process / peptidoglycan-based cell wall / modification-dependent protein catabolic process ...symbiont-mediated perturbation of host defenses / zymogen binding / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / proteolysis involved in protein catabolic process / peptidoglycan-based cell wall / modification-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / extracellular region / plasma membrane / cytoplasm
Similarity search - Function
Proteasome, alpha subunit, bacterial / Proteasome subunit beta, actinobacteria / Proteasome B-type subunit / Proteasome beta-type subunit profile. / : / Proteasome alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome subunit / Proteasome, subunit alpha/beta / Nucleophile aminohydrolases, N-terminal
Similarity search - Domain/homology
Proteasome subunit beta / Proteasome subunit alpha
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsZeytuni N / Uday AB / Vahidi S / Turner M
Funding support Canada, 2 items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT451412 Canada
Natural Sciences and Engineering Research Council (NSERC, Canada)RGPIN/03031-2022 Canada
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis for allosteric modulation of M. tuberculosis proteasome core particle.
Authors: Madison Turner / Adwaith B Uday / Algirdas Velyvis / Enrico Rennella / Natalie Zeytuni / Siavash Vahidi /
Abstract: The Mycobacterium tuberculosis (Mtb) proteasome system selectively degrades damaged or misfolded proteins and is crucial for the pathogen's survival within the host. Targeting the 20S core particle ...The Mycobacterium tuberculosis (Mtb) proteasome system selectively degrades damaged or misfolded proteins and is crucial for the pathogen's survival within the host. Targeting the 20S core particle (CP) offers a viable strategy for developing tuberculosis treatments. The activity of Mtb 20S CP, like that of its eukaryotic counterpart, is allosterically regulated, yet the specific conformations involved have not been captured in high-resolution structures to date. Here, we use single-particle electron cryomicroscopy and H/D exchange mass spectrometry to determine the Mtb 20S CP structure in an auto-inhibited state that is distinguished from the canonical resting state by the conformation of switch helices at the α/β interface. The rearrangement of these helices collapses the S1 pocket, effectively inhibiting substrate binding. Biochemical experiments show that the Mtb 20S CP activity can be altered through allosteric sites far from the active site. Our findings underscore the potential of targeting allostery to develop antituberculosis therapeutics.
History
DepositionJun 26, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45496.png

Downloads & links

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Map

FileDownload / File: emd_45496.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationD7 symmetry map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 448 pix.
= 383.04 Å		0.86 Å/pix.
x 448 pix.
= 383.04 Å		0.86 Å/pix.
x 448 pix.
= 383.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.855 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 31.100000000000001
Minimum - Maximum-28.776377 - 108.337119999999999
Average (Standard dev.)0.2124111 (±4.08212)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 383.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: D7 symmetry half map

Fileemd_45496_half_map_1.map
AnnotationD7 symmetry half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: D7 symmetry half map

Fileemd_45496_half_map_2.map
AnnotationD7 symmetry half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : 20S Proteasome core particle in complex with Ixazomib

EntireName: 20S Proteasome core particle in complex with Ixazomib
Components
  • Complex: 20S Proteasome core particle in complex with Ixazomib
    • Protein or peptide: Proteasome subunit alpha
    • Protein or peptide: Proteasome subunit beta
  • Ligand: [(1~{R})-1-[2-[[2,5-bis(chloranyl)phenyl]carbonylamino]ethanoylamino]-3-methyl-butyl]boronic acid

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Supramolecule #1: 20S Proteasome core particle in complex with Ixazomib

SupramoleculeName: 20S Proteasome core particle in complex with Ixazomib / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)

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Macromolecule #1: Proteasome subunit alpha

MacromoleculeName: Proteasome subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 14 / Enantiomer: LEVO
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Molecular weightTheoretical: 26.911039 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MSFPYFISPE QAMRERSELA RKGIARAKSV VALAYAGGVL FVAENPSRSL QKISELYDRV GFAAAGKFNE FDNLRRGGIQ FADTRGYAY DRRDVTGRQL ANVYAQTLGT IFTEQAKPYE VELCVAEVAH YGETKRPELY RITYDGSIAD EPHFVVMGGT T EPIANALK ...String:
MSFPYFISPE QAMRERSELA RKGIARAKSV VALAYAGGVL FVAENPSRSL QKISELYDRV GFAAAGKFNE FDNLRRGGIQ FADTRGYAY DRRDVTGRQL ANVYAQTLGT IFTEQAKPYE VELCVAEVAH YGETKRPELY RITYDGSIAD EPHFVVMGGT T EPIANALK ESYAENASLT DALRIAVAAL RAGSADTSGG DQPTLGVASL EVAVLDANRP RRAFRRITGS ALQALLVDQE SP QSDGESS G

UniProtKB: Proteasome subunit alpha

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Macromolecule #2: Proteasome subunit beta

MacromoleculeName: Proteasome subunit beta / type: protein_or_peptide / ID: 2 / Number of copies: 14 / Enantiomer: LEVO / EC number: proteasome endopeptidase complex
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Molecular weightTheoretical: 24.445383 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: TTIVALKYPG GVVMAGDRRS TQGNMISGRD VRKVYITDDY TATGIAGTAA VAVEFARLYA VELEHYEKLE GVPLTFAGKI NRLAIMVRG NLAAAMQGLL ALPLLAGYDI HASDPQSAGR IVSFDAAGGW NIEEEGYQAV GSGSLFAKSS MKKLYSQVTD G DSGLRVAV ...String:
TTIVALKYPG GVVMAGDRRS TQGNMISGRD VRKVYITDDY TATGIAGTAA VAVEFARLYA VELEHYEKLE GVPLTFAGKI NRLAIMVRG NLAAAMQGLL ALPLLAGYDI HASDPQSAGR IVSFDAAGGW NIEEEGYQAV GSGSLFAKSS MKKLYSQVTD G DSGLRVAV EALYDAADDD SATGGPDLVR GIFPTAVIID ADGAVDVPES RIAELARAII ESRSGADTFG SDGGEK

UniProtKB: Proteasome subunit beta

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Macromolecule #3: [(1~{R})-1-[2-[[2,5-bis(chloranyl)phenyl]carbonylamino]ethanoylam...

MacromoleculeName: [(1~{R})-1-[2-[[2,5-bis(chloranyl)phenyl]carbonylamino]ethanoylamino]-3-methyl-butyl]boronic acid
type: ligand / ID: 3 / Number of copies: 14 / Formula: 6V8
Molecular weightTheoretical: 361.029 Da
Chemical component information

ChemComp-6V8:
[(1~{R})-1-[2-[[2,5-bis(chloranyl)phenyl]carbonylamino]ethanoylamino]-3-methyl-butyl]boronic acid

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration5 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
100.0 mMNaClSodium chloride
50.0 mMNaH2PO4Sodium phosphate monobasic
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.75 µm / Nominal defocus min: 1.25 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE / Details: Ab-initio model generated in cryoSPARC
Final reconstructionApplied symmetry - Point group: D7 (2x7 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4) / Number images used: 449574
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4) / Details: Homogenous refinement in cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4) / Details: Homogenous refinement in cryoSPARC
FSC plot (resolution estimation)

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