6fkg

Crystal structure of the M.tuberculosis MbcT-MbcA toxin-antitoxin complex.

spinqualitylabelsall models 6fkg, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6fkg is a 4 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MBCT_MYCTU Toxic component of a type II toxin-antitoxin (TA) system. Neutralized by cognate antitoxin MbcA (PubMed:30315706, PubMed:30792174). Degrades NAD(+) by phosphorolysis. Expression in the absence of its cognate antitoxin MbcA causes dramatic reduction of intracellular NAD(+) levels and is deleterious to cell growth, causing cell death. In a SCID mouse infection model, mice infected with bacteria overexpressing this protein survive longer. Overexpression of this protein in a mouse infection model at 21 days leads to bacterial death, and shows a synergistic 100-fold increase in mouse survival when combined with isoniazid treatment (PubMed:30792174). Publication Abstract from PubMed Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved the 1.8 A-resolution crystal structure of the MbcTA complex. We found that MbcT resembles secreted NAD(+)-dependent bacterial exotoxins, such as diphtheria toxin. Indeed, MbcT catalyzes NAD(+) degradation in vitro and in vivo. Unexpectedly, the reaction is stimulated by inorganic phosphate, and our data reveal that MbcT is a NAD(+) phosphorylase. In the absence of MbcA, MbcT triggers rapid M. tuberculosis cell death, which reduces mycobacterial survival in macrophages and prolongs the survival of infected mice. Our study expands the molecular activities employed by bacterial TA modules and uncovers a new class of enzymes that could be exploited to treat tuberculosis and other infectious diseases. An NAD(+) Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death.,Freire DM, Gutierrez C, Garza-Garcia A, Grabowska AD, Sala AJ, Ariyachaokun K, Panikova T, Beckham KSH, Colom A, Pogenberg V, Cianci M, Tuukkanen A, Boudehen YM, Peixoto A, Botella L, Svergun DI, Schnappinger D, Schneider TR, Genevaux P, de Carvalho LPS, Wilmanns M, Parret AHA, Neyrolles O Mol Cell. 2019 Feb 18. pii: S1097-2765(19)30048-6. doi:, 10.1016/j.molcel.2019.01.028. PMID:30792174 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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