Distinct Interactions of 2′- and 3′--(-Methyl)anthraniloyl-Isomers of ATP and GTP with the Adenylyl Cyclase Toxin of , Edema Factor - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Biochemical Pharmacology Année : 2009

Distinct Interactions of 2′- and 3′--(-Methyl)anthraniloyl-Isomers of ATP and GTP with the Adenylyl Cyclase Toxin of , Edema Factor

Srividya Suryanarayana
  • Fonction : Auteur
Jenna L. Wang
  • Fonction : Auteur
Mark Richter
  • Fonction : Auteur
Yuequan Shen
  • Fonction : Auteur
Wei-Jen Tang
  • Fonction : Auteur
Gerald H. Lushington
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Roland Seifert
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Résumé

Anthrax disease is caused by the spore-forming bacterium, . produces a calmodulin-activated adenylyl cyclase (AC) toxin, edema factor (EF). Through excessive cAMP accumulation EF disrupts host defence. In a recent study (Taha et al., Mol Pharmacol 2009;75:693-703) we showed that various 2′(3′)---(methyl)anthraniloyl (MANT)-substituted nucleoside 5′-triphosphates are potent inhibitors (K values in the 0.1-5μM range) of purified EF. Upon interaction with calmodulin we observed efficient fluorescence resonance energy transfer (FRET) between tryptophan and tyrosine residues of EF and the MANT-group of MANT-ATP. Molecular modelling suggested that both the 2′- and 3′-MANT-isomers can bind to EF. The aim of the present study was to examine the effects of defined 2′- and 3′-MANT-isomers of ATP and GTP on EF. 3′-MANT-2′-deoxy-ATP inhibited EF more potently than 2′-MANT-3′-deoxy-ATP, whereas the opposite was the case for the corresponding GTP analogs. Calmodulin-dependent direct MANT-fluorescence and FRET was much larger with 2′-MANT-3′-deoxy-ATP and 2′-MANT-3′-deoxy-GTP compared to the corresponding 3′-MANT-2′-deoxy-isomers and the 2′(3′)-racemates. K values of MANT-nucleotides for inhibition of catalysis correlated with K values of MANT-nucleotides in FRET studies. Molecular modelling indicated different positioning of the MANT-group in 2′-MANT-3′-deoxy-ATP/GTP and 3′-MANT-2′-deoxy-ATP/GTP bound to EF. Collectively, EF interacts differentially with 2′-MANT- and 3′-MANT-isomers of ATP and GTP, indicative for conformational flexibility of the catalytic site and offering a novel approach for the development of potent and selective EF inhibitors. Moreover, our present study may serve as a general model of how to use MANT-nucleotide isomers for the analysis of the molecular mechanisms of nucleotide/protein interactions.
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hal-00493515 , version 1 (19-06-2010)

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Srividya Suryanarayana, Jenna L. Wang, Mark Richter, Yuequan Shen, Wei-Jen Tang, et al.. Distinct Interactions of 2′- and 3′--(-Methyl)anthraniloyl-Isomers of ATP and GTP with the Adenylyl Cyclase Toxin of , Edema Factor. Biochemical Pharmacology, 2009, 78 (3), pp.224. ⟨10.1016/j.bcp.2009.04.006⟩. ⟨hal-00493515⟩

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