Labile Zn fingers (Zfs) in proteins contain Zn-bound thiolates that can react with electrophilic agents, causing Zn(2+) ejection and protein unfolding. Such labile Zfs have been shown to be Cys4 or Cys3His cores whose Zn-bound Cys have no hydrogen bonds. Our aim here is to identify labile Zfs in proteins that are promising drug targets using these features. To prove the strategy used, we showed that five proteins with predicted labile Zfs reacted with Zn-ejecting agents, whereas five proteins with no or inert Zfs did not. The comprehensive set of labile Zfs provides new drug targets and guidelines to redesign Zn-ejecting compounds with improved specificity.
The ADP-ribosylating toxins (ADPRTs) and poly(ADP-ribose) polymerases (PARPs) are two important drug-target protein families. Although the Y-X(10)-Y motif for the diphtheria toxin group and the STS motif for the other ADPRTs have been found to recognize the NAD(+) substrate, it is not known (i) if these two different motifs share any structural similarity, (ii) the key forces/residues contributing to NAD(+) binding, and (iii) if they recognize the same or different NAD(+) conformations. Here, we show that even though the different toxin groups and PARPs share insignificant sequence identity, they share a similar 3D structure shaped like a scorpion (the "scorpion" motif) whose first three and last residues interact mainly with the NAD(+) nicotinamide ring via van der Waals forces. This locally conserved structure binds the nicotinamide mononucleotide moiety in a structurally conserved ringlike conformation. The biological implications/applications of locally conserved structures for toxins/PARPs and the nicotinamide mononucleotide are discussed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.