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Pocket analysis of the full-length cholix toxin. An assessment of the structure–dynamics of the apo catalytic domain

Cholix toxin from Vibrio cholerae is the third member of the diphtheria toxin (DT) group of mono-ADP-ribosyltransferase (mART) bacterial toxins. It shares structural and functional properties with Pseudomonas aeruginosa exotoxin A and Corynebacterium diphtheriae DT. Cholix toxin is an important model for the development of antivirulence approaches and therapeutics against these toxins from pathogenic bacteria. Herein, we have used the high-resolution X-ray structure of full-length cholix complexed with NAD+ to describe the properties of the NAD+-binding pocket at the residue level, including the role of crystallographic water molecules in the NAD+ substrate interaction. The full-length apo cholix structure is used to describe the putative NAD+-binding site(s) and to correlate biochemical with crystallographic data to study the stoichiometry and orientation of bound NAD+ molecules. We quantitatively describe the NAD+ substrate interactions on a residue basis for the main 22 pocket residues in cholixf, a glycerol and 5 contact water molecules as part of the recognition surface by the substrate according to the conditions of crystallization. In addition, the dynamic properties of an in silico version of the catalytic domain were investigated in order to understand the lack of electronic density for one of the main flexible loops (R-loop) in the pocket of X-ray complexes. Implications for a rational drug design approach for mART toxins are derived.