000172498 001__ 172498 000172498 005__ 20210129214438.0 000172498 0247_ $$2doi$$a10.1016/j.jsb.2014.10.002 000172498 0247_ $$2ISSN$$a1047-8477 000172498 0247_ $$2ISSN$$a1095-8657 000172498 0247_ $$2WOS$$aWOS:000346229500007 000172498 037__ $$aFZJ-2014-05967 000172498 082__ $$a540 000172498 1001_ $$0P:(DE-HGF)0$$aDas, Uddipan$$b0 000172498 245__ $$aCrystal structure of the VapBC-15 complex from Mycobacterium tuberculosis reveals a two-metal ion dependent PIN-domain ribonuclease and a variable mode of toxin-antitoxin assembly 000172498 260__ $$aSan Diego, Calif.$$bElsevier$$c2014 000172498 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1420462993_23887 000172498 3367_ $$2DataCite$$aOutput Types/Journal article 000172498 3367_ $$00$$2EndNote$$aJournal Article 000172498 3367_ $$2BibTeX$$aARTICLE 000172498 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000172498 3367_ $$2DRIVER$$aarticle 000172498 500__ $$aArticle in press 000172498 520__ $$aAlthough PIN (PilT N-terminal)-domain proteins are known to have ribonuclease activity, their specific mechanism of action remains unknown. VapCs form a family of ribonucleases that possess a PIN-domain assembly and are known as toxins. The activities of VapCs are impaired by VapB antitoxins. Here we present the crystal structure of the VapBC-15 toxin–antitoxin complex from Mycobacterium tuberculosis determined to 2.1 Å resolution. The VapB-15 and VapC-15 components assemble into one heterotetramer (VapB2C2) and two heterotrimers (VapBC2) in each asymmetric unit of the crystal. The active site of VapC-15 toxin consists of a cluster of acidic amino acid residues and two divalent metal ions, forming a well organised ribonuclease active site. The distribution of the catalytic-site residues of the VapC-15 toxin is similar to that of T4 RNase H and of Methanococcus jannaschii FEN-1, providing strong evidence that these three proteins share a similar mechanism of activity. The presence of both VapB2C2 and VapBC2 emphasizes the fact that the same antitoxin can bind the toxin in 1:1 and 1:2 ratios. The crystal structure determination of the VapBC-15 complex reveals for the first time a PIN-domain ribonuclease protein that shows two metal ions at the active site and a variable mode of toxin–antitoxin assembly. The structure further shows that VapB-15 antitoxin binds to the same groove meant for the binding of putative substrate (RNA), resulting in the inhibition of VapC-15’s toxicity. 000172498 536__ $$0G:(DE-HGF)POF2-452$$a452 - Structural Biology (POF2-452)$$cPOF2-452$$fPOF II$$x0 000172498 588__ $$aDataset connected to CrossRef, juser.fz-juelich.de 000172498 7001_ $$0P:(DE-HGF)0$$aPogenberg, Vivian$$b1 000172498 7001_ $$0P:(DE-Juel1)131986$$aTiruttani Subhramanyam, Udaya Kumar$$b2$$ufzj 000172498 7001_ $$0P:(DE-HGF)0$$aMatthias, Wilmanns$$b3 000172498 7001_ $$0P:(DE-HGF)0$$aGourinath, Samudrala$$b4 000172498 7001_ $$0P:(DE-HGF)0$$aSrinivana, Alagiri$$b5$$eCorresponding Author 000172498 773__ $$0PERI:(DE-600)1469822-5$$a10.1016/j.jsb.2014.10.002$$gp. 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