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Structural basis for targeting the ribosomal protein S 1 of M ycobacterium tuberculosis by pyrazinamide
Author(s) -
Yang Juanjuan,
Liu Yindi,
Bi Jing,
Cai Qixu,
Liao Xinli,
Li Wenqian,
Guo Chenyun,
Zhang Qian,
Lin Tianwei,
Zhao Yufen,
Wang Honghai,
Liu Jun,
Zhang Xuelian,
Lin Donghai
Publication year - 2015
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.12892
Subject(s) - biology , pyrazinamide , tuberculosis , ribosomal protein , ribosomal rna , ribosome , computational biology , mycobacterium tuberculosis , virology , microbiology and biotechnology , genetics , antibiotics , rifampicin , rna , pathology , gene , medicine
Summary 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 S 1 of M ycobacterium tuberculosis ( M tb ), 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 M tb and how RpsA mutations confer PZA resistance. Here, we report the crystal structures of the C ‐terminal domain of RpsA of M tb 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 ( L ys303, P he307, P he310 and A rg357) 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.