View source for 9pme


==Crystallographic structure of MazF-E24A toxin bound to SamF==
<StructureSection load='9pme' size='340' side='right'caption='[[9pme]], [[Resolution|resolution]] 1.52&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9pme]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9PME OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9PME FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.52&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></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=9pme FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9pme OCA], [https://pdbe.org/9pme PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9pme RCSB], [https://www.ebi.ac.uk/pdbsum/9pme PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9pme ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MAZF_ECOLI MAZF_ECOLI] Toxic component of a type II toxin-antitoxin (TA) module. A sequence-specific endoribonuclease it inhibits protein synthesis by cleaving mRNA and inducing bacterial stasis. It is stable, single-strand specific with mRNA cleavage independent of the ribosome, although translation enhances cleavage for some mRNAs (PubMed:18854355). Cleavage occurs at the 5'-end of ACA sequences, yielding a 2',3'-cyclic phosphate and a free 5'-OH, although cleavage can also occur on the 3'-end of the first A (PubMed:15537630, PubMed:23280569). Digests 16S rRNA in vivo 43 nts upstream of the C-terminus; this removes the anti-Shine-Dalgarno sequence forming a mixed population of wild-type and "stress ribosomes". Stress ribosomes do not translate leader-containing mRNA but are proficient in translation of leaderless mRNA, which alters the protein expression profile of the cell; MazF produces some leaderless mRNA (PubMed:21944167). The toxic endoribonuclease activity is inhibited by its labile cognate antitoxin MazE. Toxicity results when the levels of MazE decrease in the cell, leading to mRNA degradation. This effect can be rescued by expression of MazE, but after 6 hours in rich medium overexpression of MazF leads to programmed cell death (PubMed:8650219, PubMed:11222603). MazF-mediated cell death occurs following a number of stress conditions in a relA-dependent fashion and only when cells are in log phase; sigma factor S (rpoS) protects stationary phase cells from MazF-killing (PubMed:15150257, PubMed:19251848). Cell growth and viability are not affected when MazF and MazE are coexpressed. Both MazE and MazE-MazF bind to the promoter region of the mazE-mazF operon to inhibit their own transcription. MazE has higher affinity for promoter DNA in the presence of MazF (PubMed:25564525). Cross-talk can occur between different TA modules. Ectopic expression of this toxin induces transcription of the relBEF TA module operon with specific cleavage of the mRNA produced (PubMed:23432955).<ref>PMID:11071896</ref> <ref>PMID:11222603</ref> <ref>PMID:15150257</ref> <ref>PMID:15537630</ref> <ref>PMID:18854355</ref> <ref>PMID:19251848</ref> <ref>PMID:21944167</ref> <ref>PMID:23280569</ref> <ref>PMID:23432955</ref> <ref>PMID:25564525</ref> <ref>PMID:8650219</ref>   Might also serve to protect cells against bacteriophage; in the presence of MazE-MazF fewer P1 phage are produced than in a disrupted strain. For strain K38 most wild-type cells are killed but not by phage lysis; it was suggested that MazE-MazF causes P1 phage exclusion from the bacterial population. This phenomenon is strain dependent.<ref>PMID:15316771</ref>   The physiological role of this TA module is debated. Programmed cell death (PCD) occurs when cells are at high density and depends on the presence of MazE-MazF and a quorum sensing pentapeptide, the extracellular death factor (EDF) with sequence Asn-Asn-Trp-Asn-Asn (NNWNN), probably produced from the zwf gene product glucose-6-phosphate 1-dehydrogenase (PubMed:17962566, PubMed:18310334). Cell death governed by the MazE-MazF and DinJ-YafQ TA modules seems to play a role in biofilm formation, while MazE-MazF is also implicated in cell death in liquid media (PubMed:19707553). Implicated in hydroxy radical-mediated cell death induced by hydroxyurea treatment (PubMed:20005847, PubMed:23416055). In conjunction with EDF prevents apoptotic-like death (ALD) in the presence of DNA damaging agents, probably by reducing recA mRNA levels in a non-endonuclease-mediated manner (PubMed:22412352). Other studies (in strains BW25113 and MC4100, the latter makes EDF) demonstrate MazF does not cause PCD but instead bacteriostasis and possibly a dormant state as well as persister cell generation (PubMed:24375411).<ref>PMID:17962566</ref> <ref>PMID:18310334</ref> <ref>PMID:19707553</ref> <ref>PMID:20005847</ref> <ref>PMID:21419338</ref> <ref>PMID:22412352</ref> <ref>PMID:23416055</ref> <ref>PMID:24375411</ref> <ref>PMID:8650219</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cell growth regulation granted by toxin-antitoxin systems enables bacteria to fight phage infections, evade host immune defenses, and survive antibiotic treatment. In this work, a potent and specific peptide competitive inhibitor for the Escherichia coli toxin MazF was developed and named Small Antitoxin of MazF (SamF). Employing a set of N-acetylated and C-amidated synthetic peptides, biophysical methods, biochemistry, and molecular biology techniques, we demonstrated that SamF binds tightly and with high specificity to MazF in vitro and in vivo, blocking access to the substrate binding site. Coexpression of SamF with MazF in E. coli efficiently counteracted the metabolic downregulation imposed by the toxin and the formation of antibiotic persisters. Altogether, our data uncovered a new MazF druggable site and an excellent scaffold for the design of antimicrobials. SamF is also a promising tool to study MazF in vitro and its physiological function in bacteria.

Development of a Potent and Functional In Vivo Peptide Competitive Inhibitor for the Toxin MazF.,Pizzolato-Cezar LR, Vitale PM, Liria CW, Pineda MAR, Lacerda CD, Marana SR, Nascimento AFZ, Sassonia RC, Sgro GG, Salinas RK, Machini MT J Med Chem. 2025 Oct 23;68(20):21665-21682. doi: 10.1021/acs.jmedchem.5c02001. , Epub 2025 Oct 13. PMID:41081386<ref>PMID:41081386</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9pme" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli K-12]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Machini MT]]
[[Category: Nascimento AFZ]]
[[Category: Pizzolato-Cezar LR]]
[[Category: Salinas RK]]