A comparative structure-function analysis of active-site inhibitors of Vibrio cholerae cholix toxin

作者：Lugo Miguel R; Merrill A Rod^*

来源：Journal of Molecular Recognition, 2015, 28(9): 539-552.

DOI：10.1002/jmr.2469

• bacterial toxins
• exotoxin A
• Vibrio cholerae
• Pseudomonas aeruginosa
• PARP inhibitors
• NAD(+)-binding protein
• 3D-QSAR

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.

• 出版日期2015-9