1xk9

From Proteopedia

Pseudomanas exotoxin A in complex with the PJ34 inhibitor

Overview

The mono-ADPRT (mono-ADP-ribosyltransferase), Pseudomonas aeruginosa ETA, (exotoxin A), catalyses the transfer of ADP-ribose from NAD+ to its, protein substrate. A series of water-soluble compounds that structurally, mimic the nicotinamide moiety of NAD+ was investigated for their, inhibition of the catalytic domain of ETA. The importance of an amide, locked into a hetero-ring structure and a core hetero-ring system that is, planar was a trend evident by the IC50 values. Also, the weaker inhibitors, have core ring structures that are less planar and thus more flexible. One, of the most potent inhibitors, PJ34, was further characterized and shown, to exhibit competitive inhibition with an inhibition constant K(i) of 140, nM. We also report the crystal structure of the catalytic domain of ETA in, complex with PJ34, the first example of a mono-ADPRT in complex with an, inhibitor. The 2.1 A (1 A=0.1 nm) resolution structure revealed that PJ34, is bound within the nicotinamide-binding pocket and forms stabilizing, hydrogen bonds with the main chain of Gly-441 and to the side-chain oxygen, of Gln-485, a member of a proposed catalytic loop. Structural comparison, of this inhibitor complex with diphtheria toxin (a mono-ADPRT) and with, PARPs [poly(ADP-ribose) polymerases] shows similarity of the catalytic, residues; however, a loop similar to that found in ETA is present in, diphtheria toxin but not in PARP. The present study provides insight into, the important features required for inhibitors that mimic NAD+ and their, binding to the mono-ADPRT family of toxins.

About this Structure

1XK9 is a Single protein structure of sequence from Pseudomonas aeruginosa with P34 as ligand. Active as NAD(+)--diphthamide ADP-ribosyltransferase, with EC number 2.4.2.36 Full crystallographic information is available from OCA.

Reference

Structure-function analysis of water-soluble inhibitors of the catalytic domain of exotoxin A from Pseudomonas aeruginosa., Yates SP, Taylor PL, Jorgensen R, Ferraris D, Zhang J, Andersen GR, Merrill AR, Biochem J. 2005 Feb 1;385(Pt 3):667-75. PMID:15458385

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