6FKG

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

Summary for 6FKG

• Entry DOI: 10.2210/pdb6fkg/pdb
• Descriptor: Rv1989c (MbcT), Rv1990c (MbcA), GLYCEROL, ... (4 entities in total)
• Functional Keywords: toxin-antitoxin system phosphorylase nad+-binding, toxin
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 4
• Total formula weight: 66070.38

Authors

Freire, D.M.,Cianci, M.,Pogenberg, V.,Schneider, T.R.,Wilmanns, M.,Parret, A.H.A. (deposition date: 2018-01-24, release date: 2019-02-27, Last modification date: 2024-05-08)

Primary citation

Freire, D.M.,Gutierrez, C.,Garza-Garcia, A.,Grabowska, A.D.,Sala, A.J.,Ariyachaokun, K.,Panikova, T.,Beckham, K.S.H.,Colom, A.,Pogenberg, V.,Cianci, M.,Tuukkanen, A.,Boudehen, Y.M.,Peixoto, A.,Botella, L.,Svergun, D.I.,Schnappinger, D.,Schneider, T.R.,Genevaux, P.,de Carvalho, L.P.S.,Wilmanns, M.,Parret, A.H.A.,Neyrolles, O.
An NAD+Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death.
Mol.Cell, 73:1282-1291.e8, 2019

PubMed Abstract: 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 Å-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.

PubMed: 30792174
DOI: 10.1016/j.molcel.2019.01.028

Experimental method

X-RAY DIFFRACTION (1.8 Å)