6A7V

Crystal structure of Mycobacterium tuberculosis VapBC11 toxin-antitoxin complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.184 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structural, functional and biological insights into the role of Mycobacterium tuberculosis VapBC11 toxin-antitoxin system: targeting a tRNase to tackle mycobacterial adaptation.

Deep, A.Tiwari, P.Agarwal, S.Kaundal, S.Kidwai, S.Singh, R.Thakur, K.G.

(2018) Nucleic Acids Res 46: 11639-11655

  • DOI: https://doi.org/10.1093/nar/gky924
  • Primary Citation of Related Structures:  
    6A7V

  • PubMed Abstract: 

    Toxin-antitoxin (TA) systems are involved in diverse physiological processes in prokaryotes, but their exact role in Mycobacterium tuberculosis (Mtb) virulence and in vivo stress adaptation has not been extensively studied. Here, we demonstrate that the VapBC11 TA module is essential for Mtb to establish infection in guinea pigs. RNA-sequencing revealed that overexpression of VapC11 toxin results in metabolic slowdown, suggesting that modulation of the growth rate is an essential strategy for in vivo survival. Interestingly, overexpression of VapC11 resulted in the upregulation of chromosomal TA genes, suggesting the existence of highly coordinated crosstalk among TA systems. In this study, we also present the crystal structure of the VapBC11 heterooctameric complex at 1.67 Å resolution. Binding kinetic studies suggest that the binding affinities of toxin-substrate and toxin-antitoxin interactions are comparable. We used a combination of structural studies, molecular docking, mutational analysis and in vitro ribonuclease assays to enhance our understanding of the mode of substrate recognition by the VapC11 toxin. Furthermore, we have also designed peptide-based inhibitors to target VapC11 ribonuclease activity. Taken together, we propose that the structure-guided design of inhibitors against in vivo essential ribonucleases might be a novel strategy to hasten clearance of intracellular Mtb.


  • Organizational Affiliation

    Structural Biology Laboratory, G. N. Ramachandran Protein Centre, Council of Scientific and Industrial Research-Institute of Microbial Technology (CSIR-IMTECH), Chandigarh 160036, India.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ribonuclease VapC11
A, C, E, G
139Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: vapC11Rv1561MTCY48.04c
EC: 3.1
UniProt
Find proteins for P9WFA5 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WFA5 
Go to UniProtKB:  P9WFA5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WFA5
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Antitoxin VapB11B [auth K],
D,
F [auth U],
H
62Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: vapB11Rv1560MTCY48.05c
UniProt
Find proteins for P9WLU3 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WLU3 
Go to UniProtKB:  P9WLU3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WLU3
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.184 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.555α = 90
b = 127.007β = 90
c = 151.207γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Council of Scientific & Industrial ResearchIndia--

Revision History  (Full details and data files)

  • Version 1.0: 2018-10-10
    Type: Initial release
  • Version 1.1: 2019-05-01
    Changes: Data collection, Database references, Structure summary
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Refinement description