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- PDB-9jvp: CryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bo... -

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Basic information

Entry
Database: PDB / ID: 9jvp
TitleCryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bortezomib, conformation 3
Components
  • (ATP-dependent Clp protease proteolytic subunit ...) x 2
  • ATP-dependent Clp protease ATP-binding subunit ClpC1
  • Beta-casein
KeywordsHYDROLASE / Mycobacterium tuberculosis / Caseinolytic protease system / Activation
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
ADENOSINE-5'-DIPHOSPHATE / ADENOSINE-5'-TRIPHOSPHATE / Chem-BO2 / 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 H37Rv (bacteria)
Bos grunniens (domestic yak)
MethodELECTRON MICROSCOPY / single 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, 9items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 19, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ATP-dependent Clp protease ATP-binding subunit ClpC1
B: ATP-dependent Clp protease ATP-binding subunit ClpC1
C: ATP-dependent Clp protease ATP-binding subunit ClpC1
D: ATP-dependent Clp protease ATP-binding subunit ClpC1
E: ATP-dependent Clp protease ATP-binding subunit ClpC1
F: ATP-dependent Clp protease ATP-binding subunit ClpC1
M: ATP-dependent Clp protease proteolytic subunit 2
G: ATP-dependent Clp protease proteolytic subunit 2
H: ATP-dependent Clp protease proteolytic subunit 2
I: ATP-dependent Clp protease proteolytic subunit 2
J: ATP-dependent Clp protease proteolytic subunit 2
K: ATP-dependent Clp protease proteolytic subunit 2
L: ATP-dependent Clp protease proteolytic subunit 2
T: ATP-dependent Clp protease proteolytic subunit 1
N: ATP-dependent Clp protease proteolytic subunit 1
O: ATP-dependent Clp protease proteolytic subunit 1
P: ATP-dependent Clp protease proteolytic subunit 1
Q: ATP-dependent Clp protease proteolytic subunit 1
R: ATP-dependent Clp protease proteolytic subunit 1
S: ATP-dependent Clp protease proteolytic subunit 1
U: Beta-casein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)727,74655
Polymers716,40621
Non-polymers11,34034
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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ATP-dependent Clp protease proteolytic subunit ... , 2 types, 14 molecules MGHIJKLTNOPQRS

#2: Protein
ATP-dependent Clp protease proteolytic subunit 2 / Endopeptidase Clp 2


Mass: 19782.576 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis H37Rv (bacteria)
Strain: H37Rv / Gene: clpP2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P9WPC3, endopeptidase Clp
#3: Protein
ATP-dependent Clp protease proteolytic subunit 1 / Endopeptidase Clp 1


Mass: 19383.111 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis H37Rv (bacteria)
Strain: H37Rv / Gene: clpP1, clpP / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P9WPC5, endopeptidase Clp

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Protein / Protein/peptide , 2 types, 7 molecules ABCDEFU

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


Mass: 73270.336 Da / Num. of mol.: 6 / Mutation: E288A, F444S, E626A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis H37Rv (bacteria)
Strain: H37Rv / Gene: clpC1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P9WPC9
#4: Protein/peptide Beta-casein


Mass: 2624.252 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos grunniens (domestic yak) / References: UniProt: P02666

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Non-polymers , 4 types, 34 molecules

#5: Chemical
ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#6: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
#8: Chemical
ChemComp-BO2 / N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE / BORTEZOMIB


Mass: 384.237 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C19H25BN4O4 / Comment: medication*YM

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: CryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bortezomib, conformation 3
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.15 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 520973 / Symmetry type: POINT

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