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- PDB-9jvz: CryoEM structure of M. tuberculosis ClpP1P2 bound to bortezomib -

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Basic information

Entry
Database: PDB / ID: 9jvz
TitleCryoEM structure of M. tuberculosis ClpP1P2 bound to bortezomib
Components
  • ATP-dependent Clp protease proteolytic subunit 1
  • ATP-dependent Clp protease proteolytic subunit 2
KeywordsHYDROLASE / Mycobacterium tuberculosis / Caseinolytic protease system / Activation
Function / homology
Function and homology information


endopeptidase Clp / endopeptidase Clp complex / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / peptidoglycan-based cell wall / ATPase binding / serine-type endopeptidase activity / plasma membrane / cytosol
Similarity search - Function
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 / ClpP/crotonase-like domain superfamily
Similarity search - Domain/homology
Chem-BO2 / ATP-dependent Clp protease proteolytic subunit 2 / ATP-dependent Clp protease proteolytic subunit 1
Similarity search - Component
Biological speciesMycobacterium tuberculosis H37Rv (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.56 Å
AuthorsZhou, B. / Zhao, H. / Gao, Y. / Chen, W. / Zhang, T. / He, J. / Xiong, X.
Funding support China, 9items
OrganizationGrant numberCountry
Other government2021YFA1300903
Other government2021YFA1300904
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
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ATP-dependent Clp protease proteolytic subunit 1
B: ATP-dependent Clp protease proteolytic subunit 1
C: ATP-dependent Clp protease proteolytic subunit 1
D: ATP-dependent Clp protease proteolytic subunit 1
E: ATP-dependent Clp protease proteolytic subunit 1
F: ATP-dependent Clp protease proteolytic subunit 1
G: ATP-dependent Clp protease proteolytic subunit 2
H: ATP-dependent Clp protease proteolytic subunit 1
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
M: ATP-dependent Clp protease proteolytic subunit 2
N: ATP-dependent Clp protease proteolytic subunit 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)291,07428
Polymers285,69514
Non-polymers5,37914
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

#1: 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
#2: Protein
ATP-dependent Clp protease proteolytic subunit 2 / Endopeptidase Clp 2


Mass: 21430.410 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: 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 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, anticancer*YM
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 BTZ-ClpP1P2 complex
Type: COMPLEX / Entity ID: #1-#2 / 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

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.56 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 668234 / Symmetry type: POINT
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00319467
ELECTRON MICROSCOPYf_angle_d0.64726334
ELECTRON MICROSCOPYf_dihedral_angle_d4.7712737
ELECTRON MICROSCOPYf_chiral_restr0.0413059
ELECTRON MICROSCOPYf_plane_restr0.0043437

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