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5m3i

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Macrodomain of Mycobacterium tuberculosis DarG

Structural highlights

5m3i is a 4 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.17Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DARG_MYCTU Antitoxin component of a hybrid type II/IV toxin-antitoxin (TA) system. De-ADP-ribosylates DNA (probably) modified on thymidine by its cognate toxin DarT, which neutralizes the activity of DarT (PubMed:27939941). Experiments in which DarG levels are depleted lead to cell death; expression of wild-type DarG protein from M.tuberculosis or T.aquaticus restores growth. Cells depleted of DarG are more sensitive to bedaquilline (targets respiration), DNA-damaging drugs (mitomycin C, netropsin) and transcription-targeted drugs (rifabutin and rifampicin). When depleted, a DNA-damage response is induced and mutability is increased (PubMed:32634279). In E.coli the macrodomain alone neutralizes DarT toxin from non-cognate T.aquaticus. The same domain de-ADP-ribosylates genomic DNA (PubMed:34408320).^[1] ^[2] ^[3]

Publication Abstract from PubMed

The discovery and study of toxin-antitoxin (TA) systems helps us advance our understanding of the strategies prokaryotes employ to regulate cellular processes related to the general stress response, such as defense against phages, growth control, biofilm formation, persistence, and programmed cell death. Here we identify and characterize a TA system found in various bacteria, including the global pathogen Mycobacterium tuberculosis. The toxin of the system (DarT) is a domain of unknown function (DUF) 4433, and the antitoxin (DarG) a macrodomain protein. We demonstrate that DarT is an enzyme that specifically modifies thymidines on single-stranded DNA in a sequence-specific manner by a nucleotide-type modification called ADP-ribosylation. We also show that this modification can be removed by DarG. Our results provide an example of reversible DNA ADP-ribosylation, and we anticipate potential therapeutic benefits by targeting this enzyme-enzyme TA system in bacterial pathogens such as M. tuberculosis.

The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNA.,Jankevicius G, Ariza A, Ahel M, Ahel I Mol Cell. 2016 Dec 15;64(6):1109-1116. doi: 10.1016/j.molcel.2016.11.014. Epub, 2016 Dec 8. PMID:27939941^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Jankevicius G, Ariza A, Ahel M, Ahel I. The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNA. Mol Cell. 2016 Dec 15;64(6):1109-1116. doi: 10.1016/j.molcel.2016.11.014. Epub, 2016 Dec 8. PMID:27939941 doi:http://dx.doi.org/10.1016/j.molcel.2016.11.014
↑ Zaveri A, Wang R, Botella L, Sharma R, Zhu L, Wallach JB, Song N, Jansen RS, Rhee KY, Ehrt S, Schnappinger D. Depletion of the DarG antitoxin in Mycobacterium tuberculosis triggers the DNA-damage response and leads to cell death. Mol Microbiol. 2020 Oct;114(4):641-652. PMID:32634279 doi:10.1111/mmi.14571
↑ Schuller M, Butler RE, Ariza A, Tromans-Coia C, Jankevicius G, Claridge TDW, Kendall SL, Goh S, Stewart GR, Ahel I. Molecular basis for DarT ADP-ribosylation of a DNA base. Nature. 2021 Aug;596(7873):597-602. doi: 10.1038/s41586-021-03825-4. Epub 2021, Aug 18. PMID:34408320 doi:http://dx.doi.org/10.1038/s41586-021-03825-4
↑ Jankevicius G, Ariza A, Ahel M, Ahel I. The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNA. Mol Cell. 2016 Dec 15;64(6):1109-1116. doi: 10.1016/j.molcel.2016.11.014. Epub, 2016 Dec 8. PMID:27939941 doi:http://dx.doi.org/10.1016/j.molcel.2016.11.014

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5m3i"

Categories: Large Structures | Mycobacterium tuberculosis | Ariza A

@@ Line 1: / Line 1: @@
 ==Macrodomain of Mycobacterium tuberculosis DarG==
-<StructureSection load='5m3i' size='340' side='right' caption='[[5m3i]], [[Resolution|resolution]] 2.17&Aring;' scene=''>
+<StructureSection load='5m3i' size='340' side='right'caption='[[5m3i]], [[Resolution|resolution]] 2.17&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5m3i]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M3I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M3I FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5m3i]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M3I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5M3I FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></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]] 2.17&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5m3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m3i OCA], [http://pdbe.org/5m3i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m3i RCSB], [http://www.ebi.ac.uk/pdbsum/5m3i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m3i ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=5m3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m3i OCA], [https://pdbe.org/5m3i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5m3i RCSB], [https://www.ebi.ac.uk/pdbsum/5m3i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5m3i ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/DARG_MYCTU DARG_MYCTU] Antitoxin component of a hybrid type II/IV toxin-antitoxin (TA) system. De-ADP-ribosylates DNA (probably) modified on thymidine by its cognate toxin DarT, which neutralizes the activity of DarT (PubMed:27939941). Experiments in which DarG levels are depleted lead to cell death; expression of wild-type DarG protein from M.tuberculosis or T.aquaticus restores growth. Cells depleted of DarG are more sensitive to bedaquilline (targets respiration), DNA-damaging drugs (mitomycin C, netropsin) and transcription-targeted drugs (rifabutin and rifampicin). When depleted, a DNA-damage response is induced and mutability is increased (PubMed:32634279). In E.coli the macrodomain alone neutralizes DarT toxin from non-cognate T.aquaticus. The same domain de-ADP-ribosylates genomic DNA (PubMed:34408320).<ref>PMID:27939941</ref> <ref>PMID:32634279</ref> <ref>PMID:34408320</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Ariza, A]]
+[[Category: Large Structures]]
-[[Category: Adp-ribose]]
+[[Category: Mycobacterium tuberculosis]]
-[[Category: Adp-ribosylation]]
+[[Category: Ariza A]]
-[[Category: Antitoxin]]
-[[Category: Macrodomain]]
-[[Category: Toxin-antitoxin]]

5m3i

From Proteopedia

Current revision

Macrodomain of Mycobacterium tuberculosis DarG

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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