Special Issue "Structure and Function of Bacterial ADP-Ribosylation Toxins"
Deadline for manuscript submissions: closed (30 November 2020).
Interests: Enzyme reaction mechanism of the bacterial mono-ADP-ribosyltransferase family; Inhibition mechanisms and structural complexes of toxins with inhibitors; X-ray structures of protein-protein complexes involving toxins
Bacterial mono-ADP-ribosyltransferase toxins (mART toxins) belong to a family of toxins that catalyze the covalent transfer of an ADP-ribose moiety from NAD+ to a macromolecule (often protein or DNA) in a host cell, changing target activity and impairing the function and survival of the host cell. Many members are the principal causative agents in serious diseases, including cholera, whooping cough, traveler’s diarrhea, gastroenteritis, diphtheria, and secondary infections of immune-compromised individuals. Members of this family are steadily increasing and are classified into five groups based on domain organization and host target substrate: (i) the DT-group consisting of a single-chain polypeptide with an A-B dimer; (ii) the CT-group characterized by a hexameric AB5-domain; (iii) the C2-group which includes binary toxins from the Clostridium genus with AB-domain structure, but are separate polypeptides (usually); (iv) the C3-group of single-domain proteins that often modify GTP-binding proteins, RhoA, B and C at Asn-41, but also target other substrates like vimentin and Crk proteins; and finally, (v) the Pierisin-group of DNA/RNA-targeting mART toxins. Although effective inhibitors against these five classes of mART toxins have not been readily forthcoming, recently, some encouraging results pertaining to active-site competitive inhibitors that mimic the NAD+ substrate have been reported.
Bacterial mART toxins share a common structural fold composed of ~100 residues with low sequence homology formed by a core scaffold of two perpendicular β-sheets, flanked by variable helical sub-structures and exposed-loops that constitute a cleft for the binding of the NAD+ substrate. The SCOP2 database assigns mART toxins (SCOP2: 56400) to the α + β class of proteins (SCOP2: 53931) and the “unusual” ADP-ribosylation fold (SCOP2: 56398). This fold is shared with eukaryotic mART proteins, Ecto-ARTs (SCOP2: 82814), and with the C-terminal domain of poly (ADP-ribose) polymerases known as PARPs (SCOP2: 56398), among others ADP-ribosylation proteins.
The conserved mART catalytic core is amenable to new toxin discovery using bioinformatics-based techniques that exploit an expanding library of bacterial genome sequence data. This method initially featured position-specific iterative BLAST methods, followed by a comparative structural approach implementing secondary structure prediction algorithms. Presently, a bona fide structure-based approach entails comparative modeling of 3-D structures, including substrate-binding residues while using known mART toxin structures as templates.
Prof. Rod Merrill
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- Bacterial toxins
- inhibitor development
- structural biology