5m3i

Macrodomain of Mycobacterium tuberculosis DarG

spinqualitylabelsall models 5m3i, resolution 2.17Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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: CL 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). 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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