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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 <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>RimM_CTD) and the molecular mechanisms underlying <i>Mtb</i>RimM_CTD binding S19 remain elusive. Here, we report the solution structure, dynamics features of <i>Mtb</i>RimM_CTD, and its interaction with S19. <i>Mtb</i>RimM_CTD 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 <i>Mtb</i>RimM_CTD–S19 complex and indicated that the β4-β5 loop and two nonconserved key residues (D105 and H129) significantly contributed to the unique pattern of <i>Mtb</i>RimM_CTD binding S19, which might be implicated in a form of orthogonality for species-dependent RimM–S19 interaction. Our study provides the structural basis for <i>Mtb</i>RimM_CTD binding S19 and is beneficial to the further exploration of <i>Mtb</i>RimM as a potential target for the development of new anti-TB drugs.