3WDC

N-terminal domain of Mycobacterium tuberculosis ClpC1 bound to Cyclomarin A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.18 Å
  • R-Value Free: 0.159 
  • R-Value Work: 0.122 
  • R-Value Observed: 0.124 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural basis of mycobacterial inhibition by cyclomarin A

Vasudevan, D.Rao, S.P.S.Noble, C.G.

(2013) J Biol Chem 288: 30883-30891

  • DOI: https://doi.org/10.1074/jbc.M113.493767
  • Primary Citation of Related Structures:  
    3WDB, 3WDC, 3WDD, 3WDE

  • PubMed Abstract: 

    Cyclomarin A (CymA) was identified as a mycobactericidal compound targeting ClpC1. However, the target was identified based on pulldown experiments and in vitro binding data, without direct functional evidence in mycobacteria. Here we show that CymA specifically binds to the N-terminal domain of ClpC1. In addition we have determined the co-crystal structure of CymA bound to the N-terminal domain of ClpC1 to high resolution. Based on the structure of the complex several mutations were engineered into ClpC1, which showed reduced CymA binding in vitro. The ClpC1 mutants were overexpressed in mycobacteria and two showed resistance to CymA, providing the first direct evidence that ClpC1 is the target of CymA. Phe(80) is important in vitro and in cells for the ClpC1-CymA interaction and this explains why other bacteria are resistant to CymA. A model for how CymA binding to the N-terminal domain of ClpC1 leads to uncontrolled proteolysis by the associated ClpP protease machinery is discussed.


  • Organizational Affiliation

    From the Novartis Institute for Tropical Diseases, 05-01 Chromos, Singapore 138670.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Probable ATP-dependent Clp protease ATP-binding subunit153Mycobacterium tuberculosisMutation(s): 0 
Gene Names: clpC
UniProt
Find proteins for P9WPC9 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WPC9 
Go to UniProtKB:  P9WPC9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WPC9
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclomarin A7Streptomyces sp.Mutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ACT
Query on ACT

Download Ideal Coordinates CCD File 
C [auth A]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Modified Residues  5 Unique
IDChains TypeFormula2D DiagramParent
MLE
Query on MLE
B
L-PEPTIDE LINKINGC7 H15 N O2LEU
WLU
Query on WLU
B
L-PEPTIDE LINKINGC7 H15 N O3LEU
WPA
Query on WPA
B
L-PEPTIDE LINKINGC10 H13 N O3PHE
WRP
Query on WRP
B
L-PEPTIDE LINKINGC16 H22 N2 O4TRP
WVL
Query on WVL
B
L-PEPTIDE LINKINGC8 H15 N O2VAL
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.18 Å
  • R-Value Free: 0.159 
  • R-Value Work: 0.122 
  • R-Value Observed: 0.124 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 33.88α = 90
b = 58.69β = 90
c = 63.62γ = 90
Software Package:
Software NamePurpose
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-18
    Type: Initial release
  • Version 1.1: 2013-12-11
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.3: 2023-12-06
    Changes: Data collection