PDBsum entry 4nnh

Ribosomal protein

PDB id: 4nnh

Contents

Protein chains

164 a.a.

Waters ×129

PDB id:

4nnh

Name:

Ribosomal protein

Title:

Structural basis for targeting the ribosomal protein s1 of mycobacterium tuberculosis by pyrazinamide

Structure:

30s ribosomal protein s1. Chain: a, b. Fragment: unp residues 285-445. Engineered: yes

Source:

Mycobacterium smegmatis. Organism_taxid: 246196. Strain: atcc 700084 / mc(2)155. Gene: rpsa, msmeg_3833, msmei_3743. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.30Å R-factor: 0.209 R-free: 0.252

Authors:

J.Yang,Y.Liu,Q.Cai,D.Lin

Key ref:

J.Yang et al. (2015). Structural basis for targeting the ribosomal protein S1 of Mycobacterium tuberculosis by pyrazinamide. Mol Microbiol, 95, 791-803. PubMed id: 25430994 DOI: 10.1111/mmi.12892

Date:

18-Nov-13 Release date: 24-Dec-14

Protein chains

A0QYY6  (RS1_MYCS2) -  Small ribosomal subunit protein bS1 from Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155)

Seq: 479 a.a.

Struc: 164 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1111/mmi.12892

Mol Microbiol 95:791-803 (2015)

PubMed id: 25430994

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

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.

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.