4NNH

Structural basis for targeting the ribosomal protein S1 of Mycobacterium tuberculosis by pyrazinamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural basis for targeting the ribosomal protein S1 of Mycobacterium tuberculosis by pyrazinamide.

Yang, J.Liu, Y.Bi, J.Cai, Q.Liao, X.Li, W.Guo, C.Zhang, Q.Lin, T.Zhao, Y.Wang, H.Liu, J.Zhang, X.Lin, D.

(2015) Mol Microbiol 95: 791-803

  • DOI: https://doi.org/10.1111/mmi.12892
  • Primary Citation of Related Structures:  
    4NNG, 4NNH, 4NNI, 4NNK

  • PubMed Abstract: 

    Pyrazinamide (PZA) is a first-line drug for tuberculosis (TB) treatment and is responsible for shortening the duration of TB therapy. The mode of action of PZA remains elusive. RpsA, the ribosomal protein S1 of Mycobacterium tuberculosis (Mtb), was recently identified as a target of PZA based on its binding activity to pyrazinoic acid (POA), the active form of PZA. POA binding to RpsA led to the inhibition of trans-translation. However, the nature of the RpsA-POA interaction remains unknown. Key questions include why POA exhibits an exquisite specificity to RpsA of Mtb and how RpsA mutations confer PZA resistance. Here, we report the crystal structures of the C-terminal domain of RpsA of Mtb and its complex with POA, as well as the corresponding domains of two RpsA variants that are associated with PZA resistance. Structural analysis reveals that POA binds to RpsA through hydrogen bonds and hydrophobic interactions, mediated mainly by residues (Lys303, Phe307, Phe310 and Arg357) that are essential for tmRNA binding. Conformational changes induced by mutation or sequence variation at the C-terminus of RpsA abolish the POA binding activity. Our findings provide insights into the mode of action of PZA and molecular basis of PZA resistance associated with RpsA mutations.


  • Organizational Affiliation

    MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Fudan University, Shanghai, 200433, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
30S ribosomal protein S1
A, B
168Mycolicibacterium smegmatis MC2 155Mutation(s): 0 
Gene Names: rpsAMSMEG_3833MSMEI_3743
UniProt
Find proteins for A0QYY6 (Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155))
Explore A0QYY6 
Go to UniProtKB:  A0QYY6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0QYY6
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.252α = 90
b = 67.117β = 90
c = 115.689γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-12-24
    Type: Initial release
  • Version 1.1: 2015-09-09
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Refinement description
  • Version 1.3: 2024-03-20
    Changes: Data collection, Database references, Refinement description