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- EMDB-61842: CryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bo... -

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Entry
Database: EMDB / ID: EMD-61842
TitleCryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bortezomib, conformation 3
Map data
Sample
  • Complex: CryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bortezomib, conformation 3
    • Protein or peptide: ATP-dependent Clp protease ATP-binding subunit ClpC1
    • Protein or peptide: ATP-dependent Clp protease proteolytic subunit 2
    • Protein or peptide: ATP-dependent Clp protease proteolytic subunit 1
    • Protein or peptide: Beta-casein
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE
KeywordsMycobacterium tuberculosis / Caseinolytic protease system / Activation / HYDROLASE
Function / homology
Function and homology information


response to 11-deoxycorticosterone / response to dehydroepiandrosterone / negative regulation of lactation / endopeptidase Clp / endopeptidase Clp complex / potassium channel inhibitor activity / ATP-dependent peptidase activity / antioxidant activity / protein quality control for misfolded or incompletely synthesized proteins / cysteine-type endopeptidase inhibitor activity ...response to 11-deoxycorticosterone / response to dehydroepiandrosterone / negative regulation of lactation / endopeptidase Clp / endopeptidase Clp complex / potassium channel inhibitor activity / ATP-dependent peptidase activity / antioxidant activity / protein quality control for misfolded or incompletely synthesized proteins / cysteine-type endopeptidase inhibitor activity / negative regulation of tumor necrosis factor-mediated signaling pathway / response to progesterone / protein folding chaperone / peptidoglycan-based cell wall / negative regulation of canonical NF-kappaB signal transduction / Golgi lumen / negative regulation of inflammatory response / regulation of blood pressure / response to estradiol / response to heat / ATPase binding / serine-type endopeptidase activity / calcium ion binding / Golgi apparatus / protein homodimerization activity / ATP hydrolysis activity / : / ATP binding / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Casein, beta / Casein, alpha/beta / Casein / Casein alpha/beta, conserved site / Caseins alpha/beta signature. / UVR domain / UVR domain profile. / ClpA/B, conserved site 1 / Chaperonins clpA/B signature 1. / ClpA/ClpB, AAA lid domain ...Casein, beta / Casein, alpha/beta / Casein / Casein alpha/beta, conserved site / Caseins alpha/beta signature. / UVR domain / UVR domain profile. / ClpA/B, conserved site 1 / Chaperonins clpA/B signature 1. / ClpA/ClpB, AAA lid domain / AAA lid domain / : / Clp repeat (R) N-terminal domain / Clp repeat (R) domain profile. / Clp, repeat (R) domain / Clp, N-terminal domain superfamily / ClpP, Ser active site / Endopeptidase Clp serine active site. / ClpP, histidine active site / Endopeptidase Clp histidine active site. / ATP-dependent Clp protease proteolytic subunit / Clp protease proteolytic subunit /Translocation-enhancing protein TepA / Clp protease / ClpA/B family / Clp ATPase, C-terminal / C-terminal, D2-small domain, of ClpB protein / C-terminal, D2-small domain, of ClpB protein / AAA domain (Cdc48 subfamily) / ClpP/crotonase-like domain superfamily / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Beta-casein / ATP-dependent Clp protease proteolytic subunit 2 / ATP-dependent Clp protease proteolytic subunit 1 / ATP-dependent Clp protease ATP-binding subunit ClpC1
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria) / Mycobacterium tuberculosis H37Rv (bacteria) / Bos grunniens (domestic yak)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.15 Å
AuthorsZhou B / Zhao H / Gao Y / Chen X / Zhang T / He J / Xiong X
Funding support China, 9 items
OrganizationGrant numberCountry
Other government2021YFA1300903
Other government2021YFA1300903
National Natural Science Foundation of China (NSFC)32300152 China
National Natural Science Foundation of China (NSFC)81973372 China
National Natural Science Foundation of China (NSFC)32170189 China
National Natural Science Foundation of China (NSFC)32241021 China
National Natural Science Foundation of China (NSFC)82341085 China
Other government2022A1515110505
Other government2022M723164
CitationJournal: Nat Commun / Year: 2025
Title: Structural Insights into Bortezomib-Induced Activation of the Caseinolytic Chaperone-Protease System in Mycobacterium tuberculosis.
Authors: Biao Zhou / Yamin Gao / Heyu Zhao / Banghui Liu / Han Zhang / Cuiting Fang / Hang Yuan / Jingjing Wang / Zimu Li / Yi Zhao / Xiaodong Huang / Xiyue Wang / A Sofia F Oliveira / James Spencer ...Authors: Biao Zhou / Yamin Gao / Heyu Zhao / Banghui Liu / Han Zhang / Cuiting Fang / Hang Yuan / Jingjing Wang / Zimu Li / Yi Zhao / Xiaodong Huang / Xiyue Wang / A Sofia F Oliveira / James Spencer / Adrian J Mulholland / Steven G Burston / Jinxing Hu / Ning Su / Xinwen Chen / Jun He / Tianyu Zhang / Xiaoli Xiong /
Abstract: The caseinolytic protease (Clp) system has recently emerged as a promising anti-tuberculosis target. The anti-cancer drug bortezomib exhibits potent anti-mycobacterial activity and binds to ...The caseinolytic protease (Clp) system has recently emerged as a promising anti-tuberculosis target. The anti-cancer drug bortezomib exhibits potent anti-mycobacterial activity and binds to Mycobacterium tuberculosis (Mtb) Clp protease complexes. We determine cryo-EM structures of Mtb ClpP1P2, ClpC1P1P2 and ClpXP1P2 complexes bound to bortezomib in different conformations. Structural and biochemical data indicate that sub-stoichiometric binding by bortezomib to the protease active sites orthosterically activates the MtbClpP1P2 complex. Bortezomib activation of MtbClpP1P2 induces structural changes promoting the recruitment of the chaperone-unfoldases, MtbClpC1 or MtbClpX, facilitating holoenzyme formation. The structures of the MtbClpC1P1P2 holoenzyme indicate that MtbClpC1 motion, induced by ATP rebinding at the MtbClpC1 spiral seam, translocates the substrate. In the MtbClpXP1P2 holoenzyme structure, we identify a specialized substrate channel gating mechanism involving the MtbClpX pore-2 loop and MtbClpP2 N-terminal domains. Our results provide insights into the intricate regulation of the Mtb Clp system and suggest that bortezomib can disrupt this regulation by sub-stoichiometric binding at the Mtb Clp protease sites.
History
DepositionOct 9, 2024-
Header (metadata) releaseMar 19, 2025-
Map releaseMar 19, 2025-
UpdateApr 8, 2026-
Current statusApr 8, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_61842.png

Downloads & links

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Map

FileDownload / File: emd_61842.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.71 Å/pix.
x 512 pix.
= 363.52 Å		0.71 Å/pix.
x 512 pix.
= 363.52 Å		0.71 Å/pix.
x 512 pix.
= 363.52 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.71 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.07821393 - 0.7604912
Average (Standard dev.)0.0014289728 (±0.015314496)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 363.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_61842_msk_1.map
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Half map: #2

Fileemd_61842_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_61842_half_map_2.map
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Sample components

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Entire : CryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bo...

EntireName: CryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bortezomib, conformation 3
Components
  • Complex: CryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bortezomib, conformation 3
    • Protein or peptide: ATP-dependent Clp protease ATP-binding subunit ClpC1
    • Protein or peptide: ATP-dependent Clp protease proteolytic subunit 2
    • Protein or peptide: ATP-dependent Clp protease proteolytic subunit 1
    • Protein or peptide: Beta-casein
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE

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Supramolecule #1: CryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bo...

SupramoleculeName: CryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bortezomib, conformation 3
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)

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Macromolecule #1: ATP-dependent Clp protease ATP-binding subunit ClpC1

MacromoleculeName: ATP-dependent Clp protease ATP-binding subunit ClpC1 / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Mycobacterium tuberculosis H37Rv (bacteria) / Strain: H37Rv
Molecular weightTheoretical: 73.270336 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: SLVLDQFGRN LTAAAMEGKL DPVIGREKEI ERVMQVLSRR TKNNPVLIGE PGVGKTAVVE GLAQAIVHGE VPETLKDKQL YTLDLGSLV AGSRYRGDFE ERLKKVLKEI NTRGDIILFI DALHTLVGAG AAEGAIDAAS ILKPKLARGE LQTIGATTLD E YRKYIEKD ...String:
SLVLDQFGRN LTAAAMEGKL DPVIGREKEI ERVMQVLSRR TKNNPVLIGE PGVGKTAVVE GLAQAIVHGE VPETLKDKQL YTLDLGSLV AGSRYRGDFE ERLKKVLKEI NTRGDIILFI DALHTLVGAG AAEGAIDAAS ILKPKLARGE LQTIGATTLD E YRKYIEKD AALERRFQPV QVGEPTVEHT IEILKGLRDR YEAHHRVSIT DAAMVAAATL ADRYINDRFL PDKAIDLIDE AG ARMRIRR MTAPPDLREF DEKIAEARRE KESAIDAQDS EKAASLRDRE KTLVAQRAER EKQWRSGDLD VVAEVDDEQI AEV LGNWTG IPVFKLTEAE TTRLLRMEEE LHKRIIGQED AVKAVSKAIR RTRAGLKDPK RPSGSFIFAG PSGVGKTELS KALA NFLFG DDDALIQIDM GEFHDRFTAS RLFGAPPGYV GYEEGGQLTE KVRRKPFSVV LFDAIEKAHQ EIYNSLLQVL EDGRL TDGQ GRTVDFKNTV LIFTSNLGTS DISKPVGLGF SKGGGENDYE RMKQKVNDEL KKHFRPEFLN RIDDIIVFHQ LTREEI IRM VDLMISRVAG QLKSKDMALV LTDAAKALLA KRGFDPVLGA RPLRRTIQRE IEDQLSEKIL FEEVGPGQVV TVDVDNW DG EGPGEDAVFT FTGTR

UniProtKB: ATP-dependent Clp protease ATP-binding subunit ClpC1

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Macromolecule #2: ATP-dependent Clp protease proteolytic subunit 2

MacromoleculeName: ATP-dependent Clp protease proteolytic subunit 2 / type: protein_or_peptide / ID: 2 / Number of copies: 7 / Enantiomer: LEVO / EC number: endopeptidase Clp
Source (natural)Organism: Mycobacterium tuberculosis H37Rv (bacteria) / Strain: H37Rv
Molecular weightTheoretical: 19.782576 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
NPYNKLFEER IIFLGVQVDD ASANDIMAQL LVLESLDPDR DITMYINSPG GGFTSLMAIY DTMQYVRADI QTVCLGQAAS AAAVLLAAG TPGKRMALPN ARVLIHQPSL SGVIQGQFSD LEIQAAEIER MRTLMETTLA RHTGKDAGVI RKDTDRDKIL T AEEAKDYG IIDTVLEYRK LS

UniProtKB: ATP-dependent Clp protease proteolytic subunit 2

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Macromolecule #3: ATP-dependent Clp protease proteolytic subunit 1

MacromoleculeName: ATP-dependent Clp protease proteolytic subunit 1 / type: protein_or_peptide / ID: 3 / Number of copies: 7 / Enantiomer: LEVO / EC number: endopeptidase Clp
Source (natural)Organism: Mycobacterium tuberculosis H37Rv (bacteria) / Strain: H37Rv
Molecular weightTheoretical: 19.383111 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
SLTDSVYERL LSERIIFLGS EVNDEIANRL CAQILLLAAE DASKDISLYI NSPGGSISAG MAIYDTMVLA PCDIATYAMG MAASMGEFL LAAGTKGKRY ALPHARILMH QPLGGVTGSA ADIAIQAEQF AVIKKEMFRL NAEFTGQPIE RIEADSDRDR W FTAAEALE YGFVDHIITR

UniProtKB: ATP-dependent Clp protease proteolytic subunit 1

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Macromolecule #4: Beta-casein

MacromoleculeName: Beta-casein / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos grunniens (domestic yak)
Molecular weightTheoretical: 2.624252 KDa
SequenceString:
MKVLILACLV ALALARELEE LNVP

UniProtKB: Beta-casein

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Macromolecule #5: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 8 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #6: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 6 / Number of copies: 8 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #7: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 7 / Number of copies: 4 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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Macromolecule #8: N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL...

MacromoleculeName: N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE
type: ligand / ID: 8 / Number of copies: 14 / Formula: BO2
Molecular weightTheoretical: 384.237 Da
Chemical component information

ChemComp-BO2:
N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE / medication, anticancer*YM

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k 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: 2.4 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6vgq

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.15 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 520973
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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