4nnk

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

spinqualitylabelsall models 4nnk, resolution 2.31Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4nnk is a 1 chain structure with sequence from Myctu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 4nng, 4nnh, 4nni Gene: MTCY01B2.22, rpsA, Rv1630 (MYCTU) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [RS1_MYCTU] Binds mRNA; thus facilitating recognition of the initiation point. It is needed to translate mRNA with a short Shine-Dalgarno (SD) purine-rich sequence (By similarity). Publication Abstract from PubMed 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. Structural basis for targeting the ribosomal protein S1 of Mycobacterium tuberculosis by pyrazinamide.,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 Mol Microbiol. 2015 Mar;95(5):791-803. doi: 10.1111/mmi.12892. Epub 2015 Jan 16. PMID:25430994 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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