4NNK

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

4NNK の概要

• エントリーDOI: 10.2210/pdb4nnk/pdb
• 関連するPDBエントリー: 4NNG 4NNH 4NNI
• 分子名称: 30S ribosomal protein S1 (2 entities in total)
• 機能のキーワード: beta barrel, ribosomal protein
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18409.51

構造登録者

Yang, J.,Liu, Y.,Cai, Q.,Lin, D. (登録日: 2013-11-18, 公開日: 2014-12-24, 最終更新日: 2024-03-20)

主引用文献

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.
Structural basis for targeting the ribosomal protein S1 of Mycobacterium tuberculosis by pyrazinamide.
Mol.Microbiol., 95:791-803, 2015

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.

PubMed: 25430994
DOI: 10.1111/mmi.12892

実験手法

X-RAY DIFFRACTION (2.31 Å)