Structural Basis for the C-Terminal Domain of Mycobacterium tuberculosis Ribosome Maturation Factor RimM to Bind Ribosomal Protein S19.

Haoran Zhang,Xinli Liao,Donghai Lin,Huilin Wang,Liubin Feng,Chenyun Guo,Qiuxiang Zhou

doi:10.3390/biom11040597

Abstract

Multidrug-resistant tuberculosis (TB) is a serious threat to public health, calling for the development of new anti-TB drugs. Chaperon protein RimM, involved in the assembly of ribosomal protein S19 into 30S ribosomal subunit during ribosome maturation, is a potential drug target for TB treatment. The C-terminal domain (CTD) of RimM is primarily responsible for binding S19. However, both the CTD structure of RimM from Mycobacterium tuberculosis (MtbRimMCTD) and the molecular mechanisms underlying MtbRimMCTD binding S19 remain elusive. Here, we report the solution structure, dynamics features of MtbRimMCTD, and its interaction with S19. MtbRimMCTD has a rigid hydrophobic core comprised of a relatively conservative six-strand β-barrel, tailed with a short α-helix and interspersed with flexible loops. Using several biophysical techniques including surface plasmon resonance (SPR) affinity assays, nuclear magnetic resonance (NMR) assays, and molecular docking, we established a structural model of the MtbRimMCTD–S19 complex and indicated that the β4-β5 loop and two nonconserved key residues (D105 and H129) significantly contributed to the unique pattern of MtbRimMCTD binding S19, which might be implicated in a form of orthogonality for species-dependent RimM–S19 interaction. Our study provides the structural basis for MtbRimMCTD binding S19 and is beneficial to the further exploration of MtbRimM as a potential target for the development of new anti-TB drugs.

Highlights

As a deadly infectious disease, tuberculosis (TB) infected about 10 million people and caused an estimated 1.4 million deaths worldwide in 2019, and the responsible pathogen for TB is Mycobacterium tuberculosis (Mtb) [1]
The RimM protein family is included in various bacterial species, but no ortholog is available in humans
Based on the identified S19 binding sites on MtbRimMCTD, which were verified by mutagenesis experiments, we established a structural model of the MtbRimMCTD –S19 complex by molecular docking to illustrate the unique pattern of MtbRimMCTD binding S19

Summary

Introduction

As a deadly infectious disease, tuberculosis (TB) infected about 10 million people and caused an estimated 1.4 million deaths worldwide in 2019, and the responsible pathogen for TB is Mycobacterium tuberculosis (Mtb) [1]. TB has developed resistance to traditional anti-TB drugs like isoniazid and rifampicin, an unfortunate complication to TB prevention and treatment [2,3]. With the emergence and spread of MDR-TB strains, it is imminent to find clinical targets for developing new antimicrobials against Mtb. RimM, an important ribosome maturation factor protein existing in Mtb, is a candidate target for anti-TB drugs. Researches have been extensively conducted on explicit functions of RimM serving as one of bacterial biogenesis factors active in the ribosome assembly process [4]. Knockout of the RimM gene caused a significant decrease in cell growth rate, accumulation of 16S rRNA precursors and ribosomal intermediates, and a reduction of polysome level [5,6,7,8].

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Conclusion