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

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.

Comprehensive essentiality analysis of the Mycobacterium kansasii genome by saturation transposon mutagenesis and deep sequencing

“…The observation that a rimM gene knockout significantly impacts bacterial growth ( 77 ) and that humans lack an ortholog of RimM has led to recent studies of the protein as a potential drug target in Mtb . These studies have provided the structural basis for Mtb RimM–ribosomal protein S19 interaction and predicted the druggability of the resulting complex ( 78 ). Again, we found no apparent paralogs of RimM in the Mk genome to explain the lack of requirement of its gene for wild-type growth in vitro .…”

The Mechanism of Action of Ginkgolic Acid (15:1) against Gram-Positive Bacteria Involves Cross Talk with Iron Homeostasis

“…Among the differentially expressed proteins, 11 structural components of ribosome-related proteins, including 50S ribosomal proteins L5, L6, L9, L11, L14, L19, L23, and L29, ribosomal protein S3, and 30S ribosomal proteins S10 and S11, were downregulated when E. faecalis was treated with GA (15:1). Ribosomal subunit interface protein YfiA, which is associated with ribosome dimerization ( 22 ), RimM, which is associated with the assembly of ribosomal protein S19 into the 30S ribosomal subunit during ribosome maturation ( 23 ), ribosome-binding factor A (RbfA) ( 24 ), and 50S ribosomal subunit assembly factor BipA, were also downregulated with GA (15:1) treatment. In addition to the canonical ribosome structural proteins, there were decreased amounts of enzymes involved in aminoacyl-tRNA biosynthesis and tRNA modification processes, such as asparagine-tRNA ligase, histidine-tRNA ligase, leucine-tRNA ligase, tyrosine-tRNA ligase 1, and tRNA uridine(34) hydroxylase.…”

Structural insights into the regulation mechanism of Mycobacterium tuberculosis MftR

“…2 The lengthy 6-month antibiotic regimen comprising today's standard tuberculosis treatment risks drug resistance, treatment failure, and subsequent transition to more toxic, costly salvage therapies. 50 As drug resistance severely threatens antibiotic therapeutic and discovery efforts against infection by bacteria, 51,52 including Mycobacterium tuberculosis, 53,54 understanding the drug resistance-related mechanisms is of paramount importance. In the case of Mycobacterium tuberculosis, a contributing factor is the formation of granulomas during infection, which plunges the bacteria into a hypoxic environment.…”