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- PDB-9if4: Structure of the Mycobacterium Tuberculosis ClpC1P1P2 complex bou... -

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Basic information

Entry
Database: PDB / ID: 9if4
TitleStructure of the Mycobacterium Tuberculosis ClpC1P1P2 complex bound to the activator Bz-Leu-Leu
Components
  • (ATP-dependent Clp protease proteolytic subunit ...) x 2
  • ATP-dependent Clp protease ATP-binding subunit ClpC1
  • Unknown peptide
  • activator Bz-Leu-Leu
KeywordsCHAPERONE / protein quality control / peptide activator / protease / ATPase
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 / protein folding chaperone / ATPase binding / serine-type endopeptidase activity / protein homodimerization activity / ATP hydrolysis activity ...endopeptidase Clp / endopeptidase Clp complex / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / peptidoglycan-based cell wall / protein folding chaperone / ATPase binding / serine-type endopeptidase activity / protein homodimerization activity / ATP hydrolysis activity / ATP binding / plasma membrane / cytosol
Similarity search - Function
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 ...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 / 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)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsWeinhaeupl, K. / Semchonok, D. / Gragera, M. / Arranz, R. / Bueno Carrasco, M.T. / Fraga, H.
Funding support1items
OrganizationGrant numberCountry
Other governmentInstruct-ERIC 30641, 26164
CitationJournal: Cell Rep / Year: 2026
Title: Activation mechanism and structural assembly of the Mycobacterium tuberculosis ClpP1P2 protease and its associated ATPases.
Authors: Katharina Weinhäupl / Tatos Akopian / Dmitry A Semchonok / Olga Krandor / Rocío Arranz / M Teresa Bueno-Carrasco / Marcos Gragera / Maelenn Chevreuil / Bertrand Raynal / Samuel Zinga / ...Authors: Katharina Weinhäupl / Tatos Akopian / Dmitry A Semchonok / Olga Krandor / Rocío Arranz / M Teresa Bueno-Carrasco / Marcos Gragera / Maelenn Chevreuil / Bertrand Raynal / Samuel Zinga / Yuxin Liu / Jack Lai / WenGen Wu / William Bachovchin / Diego Gauto / Alfred Goldberg / Eric Rubin / Hugo Fraga /
Abstract: Supramolecular assemblies are fundamental to cellular biochemical processes, relying on their dynamic nature to perform essential functions. The protease ClpP1P2, in association with ATPase partners ...Supramolecular assemblies are fundamental to cellular biochemical processes, relying on their dynamic nature to perform essential functions. The protease ClpP1P2, in association with ATPase partners ClpC1 or ClpX, is critical for the survival of Mycobacterium tuberculosis (Mtb). While the ClpP1P2 complex requires activation by specific N-blocked dipeptides to exhibit proteolytic activity in vitro, the mechanism of in vivo activation remains unclear. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the ClpC1P1P2 complex, revealing a highly asymmetric architecture with ClpC1 bound to the ClpP1P2 protease barrel. The activator dipeptide is observed only in the ClpP2 active site, while the ClpP1 entry pore remains closed. Molecular crowding agents promote the formation of larger ClpXP1P2 and ClpC1P1P2 complexes, enhancing structural stability and enzymatic activity. These findings suggest that molecular crowding stabilizes these complexes and promotes their activation, providing new insights into ClpC1P1P2 structural dynamics and function.
History
DepositionFeb 17, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 27, 2025Provider: repository / Type: Initial release
Revision 1.0Aug 27, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 27, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Aug 27, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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 / _em_admin.last_update
Revision 1.1Sep 9, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
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 / _em_admin.last_update

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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
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
L: ATP-dependent Clp protease proteolytic subunit 2
M: ATP-dependent Clp protease proteolytic subunit 2
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
T: ATP-dependent Clp protease proteolytic subunit 1
K: ATP-dependent Clp protease proteolytic subunit 2
U: activator Bz-Leu-Leu
V: activator Bz-Leu-Leu
W: activator Bz-Leu-Leu
Y: activator Bz-Leu-Leu
Z: activator Bz-Leu-Leu
a: activator Bz-Leu-Leu
b: activator Bz-Leu-Leu
X: Unknown peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)741,76940
Polymers736,00228
Non-polymers5,76612
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 6 molecules ABCDEF

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


Mass: 73575.680 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: clpC1, Rv3596c, MTCY07H7B.26 / Production host: Escherichia coli (E. coli) / References: UniProt: P9WPC9

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

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


Mass: 21914.957 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: clpP2, Rv2460c, MTV008.16c / Production host: Escherichia coli (E. coli) / References: UniProt: P9WPC3, endopeptidase Clp
#3: Protein
ATP-dependent Clp protease proteolytic subunit 1 / Endopeptidase Clp 1


Mass: 19496.270 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: clpP1, clpP, Rv2461c, MTV008.17c / Production host: Escherichia coli (E. coli) / References: UniProt: P9WPC5, endopeptidase Clp

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Protein/peptide , 2 types, 8 molecules UVWYZabX

#4: Protein/peptide
activator Bz-Leu-Leu


Mass: 348.437 Da / Num. of mol.: 7 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#5: Protein/peptide Unknown peptide


Mass: 2230.741 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Production host: Escherichia coli (E. coli)

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Non-polymers , 2 types, 12 molecules

#6: 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
#7: 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

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Details

Has ligand of interestY
Has protein modificationY

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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: ClpC1P1P2 / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER/RHODIUM / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: OTHER / Temperature (max): 77 K / Temperature (min): 77 K
Image recordingElectron dose: 46 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1cryoSPARC4.6.0particle selection
4cryoSPARC4.6.0CTF correctionPatch CTF
9PHENIX1.21.1_5286model refinement
10cryoSPARC4.6.0initial Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1372648
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.09 Å / Resolution method: OTHER / Num. of particles: 71218 / Algorithm: FOURIER SPACE
Details: Average of the two focused maps that have been used to build the composite map. For the focused maps the FSC at 0.143 CUT-OFF has been used
Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 56.12 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.005945795
ELECTRON MICROSCOPYf_angle_d0.515661809
ELECTRON MICROSCOPYf_chiral_restr0.0417128
ELECTRON MICROSCOPYf_plane_restr0.00557958
ELECTRON MICROSCOPYf_dihedral_angle_d6.82986395

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