title: A comparative structure-function analysis of active-site inhibitors of Vibrio cholerae cholix toxin.
abstract: Cholix toxin from Vibrio cholerae is a novel mono-ADP-ribosyltransferase (mART) toxin that shares structural and functional properties with Pseudomonas aeruginosa exotoxin A and Corynebacterium diphtheriae diphtheria toxin. Herein, we have used the high-resolution X-ray structure of full-length cholix toxin in the apo form, NAD(+) bound, and 10 structures of the cholix catalytic domain (C-domain) complexed with several strong inhibitors of toxin enzyme activity (NAP, PJ34, and the P-series) to study the binding mode of the ligands. A pharmacophore model based on the active pose of NAD(+) was compared with the active conformation of the inhibitors, which revealed a cationic feature in the side chain of the inhibitors that may determine the active pose. Moreover, a conformational search was conducted for the missing coordinates of one of the main active-site loops (R-loop). The resulting structural models were used to evaluate the interaction energies and for 3D-QSAR modeling. Implications for a rational drug design approach for mART toxins were derived.
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1, Canada.
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Lugo
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1, Canada.
authors.forename: A Rod
authors.initials: AR
authors.lastname: Merrill
mesh_terms: D020727:ADP-Ribosylation Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014734:Vibrio cholerae / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D009243:NAD; D020727:ADP-Ribosylation Factors; C529269:cholix toxin, Vibrio cholerae
keywords: 3D-QSAR; NAD+-binding protein; PARP inhibitors; Pseudomonas aeruginosa; Vibrio cholerae; bacterial toxins; exotoxin A