4QLP

Atomic structure of tuberculosis necrotizing toxin (TNT) complexed with its immunity factor IFT

Summary for 4QLP

• Entry DOI: 10.2210/pdb4qlp/pdb
• Descriptor: immunity factor IFT, Alanine and proline rich protein, tuberculosis necrotizing toxin (TNT) (3 entities in total)
• Functional Keywords: duf4237, nad-binding domain, b-nad+ glycohydrolase, factor rv3902c renamed here as immunity factor of tnt, membrane, hydrolase-protein binding complex, hydrolase/protein binding
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 2
• Total formula weight: 42614.48

Authors

Cingolani, G.,Lokareddy, R.K.,Sun, J.,Siroy, A.,Speer, A.,Doornbos, K.S.,Niederweis, M. (deposition date: 2014-06-12, release date: 2015-07-22, Last modification date: 2023-09-20)

Primary citation

Sun, J.,Siroy, A.,Lokareddy, R.K.,Speer, A.,Doornbos, K.S.,Cingolani, G.,Niederweis, M.
The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.
Nat.Struct.Mol.Biol., 22:672-678, 2015

PubMed Abstract: Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT), which induces necrosis by an unknown mechanism. Here we show that TNT gains access to the cytosol of Mtb-infected macrophages, where it hydrolyzes the essential coenzyme NAD(+). Expression or injection of a noncatalytic TNT mutant showed no cytotoxicity in macrophages or in zebrafish zygotes, respectively, thus demonstrating that the NAD(+) glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, Mtb produces an immunity factor for TNT (IFT) that binds TNT and inhibits its activity. The crystal structure of the TNT-IFT complex revealed a new NAD(+) glycohydrolase fold of TNT, the founding member of a toxin family widespread in pathogenic microorganisms.

PubMed: 26237511
DOI: 10.1038/nsmb.3064

Experimental method

X-RAY DIFFRACTION (1.1 Å)