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PDBsum entry 4nnh
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Ribosomal protein
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PDB id
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4nnh
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References listed in PDB file
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Key reference
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Title
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Structural basis for targeting the ribosomal protein s1 of mycobacterium tuberculosis by pyrazinamide.
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Authors
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J.Yang,
Y.Liu,
J.Bi,
Q.Cai,
X.Liao,
W.Li,
C.Guo,
Q.Zhang,
T.Lin,
Y.Zhao,
H.Wang,
J.Liu,
X.Zhang,
D.Lin.
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Ref.
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Mol Microbiol, 2015,
95,
791-803.
[DOI no: ]
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PubMed id
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Abstract
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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.
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