1XK9

Pseudomanas exotoxin A in complex with the PJ34 inhibitor

1XK9 の概要

• エントリーDOI: 10.2210/pdb1xk9/pdb
• 関連するPDBエントリー: 1AER
• 分子名称: Exotoxin A, N~2~,N~2~-DIMETHYL-N~1~-(6-OXO-5,6-DIHYDROPHENANTHRIDIN-2-YL)GLYCINAMIDE (3 entities in total)
• 機能のキーワード: toxin, adp-ribosylation, inhibitor, transferase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 47516.98

構造登録者

Yates, S.P.,Taylor, P.J.,Joergensen, R.,Ferrraris, D.,Zhang, J.,Andersen, G.R.,Merrill, A.R. (登録日: 2004-09-28, 公開日: 2005-05-17, 最終更新日: 2023-10-25)

主引用文献

Yates, S.P.,Taylor, P.J.,Joergensen, R.,Ferrraris, D.,Zhang, J.,Andersen, G.R.,Merrill, A.R.
Structure-function analysis of water-soluble inhibitors of the catalytic domain of exotoxin A from Pseudomonas aeruginosa
BIOCHEM.J., 385:667-675, 2005

PubMed Abstract: 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.

PubMed: 15458385
DOI: 10.1042/BJ20041480

実験手法

X-RAY DIFFRACTION (2.1 Å)