4nnh: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4nnh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_smegmatis_MC2_155 Mycolicibacterium smegmatis MC2 155]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NNH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NNH FirstGlance]. <br>
<table><tr><td colspan='2'>[[4nnh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_smegmatis_MC2_155 Mycolicibacterium smegmatis MC2 155]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NNH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NNH FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4nnh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nnh OCA], [https://pdbe.org/4nnh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nnh RCSB], [https://www.ebi.ac.uk/pdbsum/4nnh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nnh ProSAT]</span></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4nnh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nnh OCA], [https://pdbe.org/4nnh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nnh RCSB], [https://www.ebi.ac.uk/pdbsum/4nnh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nnh ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/RS1_MYCS2 RS1_MYCS2] Binds mRNA, facilitating recognition of most mRNAs by the 30S ribosomal subunit during translation initiation (By similarity). Plays a role in trans-translation; binds tmRNA (the product of the ssrA gene) (PubMed:25430994). Binds very poorly to pyrazinoic acid (POA), the active form of the prodrug pyrazinamide (PZA); POA does not disrupt trans-translation in this organism (PubMed:21835980). M.smegmatis is resistant to the antibiotic PZA (PubMed:25430994). In trans-translation Ala-aminoacylated transfer-messenger RNA (tmRNA, product of the ssrA gene; the 2 termini fold to resemble tRNA(Ala) while it encodes a short internal open reading frame (the tag peptide)) acts like a tRNA, entering the A-site of the ribosome and displacing the stalled mRNA (which is subsequently degraded). The ribosome then switches to translate the ORF on the tmRNA, the nascent peptide is terminated with the 'tag peptide' encoded by the tmRNA and thus targeted for degradation.[UniProtKB:P0AG67]<ref>PMID:21835980</ref> <ref>PMID:25430994</ref>  
[https://www.uniprot.org/uniprot/RS1_MYCS2 RS1_MYCS2] Binds mRNA, facilitating recognition of most mRNAs by the 30S ribosomal subunit during translation initiation (By similarity). Plays a role in trans-translation; binds tmRNA (the product of the ssrA gene) (PubMed:25430994). Binds very poorly to pyrazinoic acid (POA), the active form of the prodrug pyrazinamide (PZA); POA does not disrupt trans-translation in this organism (PubMed:21835980). M.smegmatis is resistant to the antibiotic PZA (PubMed:25430994). In trans-translation Ala-aminoacylated transfer-messenger RNA (tmRNA, product of the ssrA gene; the 2 termini fold to resemble tRNA(Ala) while it encodes a short internal open reading frame (the tag peptide)) acts like a tRNA, entering the A-site of the ribosome and displacing the stalled mRNA (which is subsequently degraded). The ribosome then switches to translate the ORF on the tmRNA, the nascent peptide is terminated with the 'tag peptide' encoded by the tmRNA and thus targeted for degradation.[UniProtKB:P0AG67]<ref>PMID:21835980</ref> <ref>PMID:25430994</ref>  
<div style="background-color:#fffaf0;">
== 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<ref>PMID:25430994</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4nnh" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==

Latest revision as of 08:57, 20 March 2024

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

4nnh, resolution 2.30Å

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