title: Conserved structural motif for recognizing nicotinamide adenine dinucleotide in poly(ADP-ribose) polymerases and ADP-ribosylating toxins: implications for structure-based drug design.
abstract: 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.
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Lee
authors.forename: C Satheesan
authors.initials: CS
authors.lastname: Babu
authors.forename: Yao Chi
authors.initials: YC
authors.lastname: Chen
authors.forename: Milos
authors.initials: M
authors.lastname: Milcic
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qu
authors.forename: Carmay
authors.initials: C
authors.lastname: Lim
mesh_terms: D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020816:Amino Acid Motifs; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D017124:Conserved Sequence; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D001427:Bacterial Toxins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D036002:ADP Ribose Transferases; D011065:Poly(ADP-ribose) Polymerases