Distinct Interactions of 2′- and 3′-O-(N-Methyl)anthraniloyl-Isomers of ATP and GTP with the Adenylyl Cyclase Toxin of Bacillus anthracis, Edema Factor
dc.contributor.author | Suryanarayana, Srividya | |
dc.contributor.author | Wang, Jenna L. | |
dc.contributor.author | Richter, Mark | |
dc.contributor.author | Shen, Yuequan | |
dc.contributor.author | Tang, Wei-Jen | |
dc.contributor.author | Lushington, Gerald H. | |
dc.contributor.author | Seifert, Roland | |
dc.date.accessioned | 2017-01-27T20:10:08Z | |
dc.date.available | 2017-01-27T20:10:08Z | |
dc.date.issued | 2009-08-01 | |
dc.identifier.citation | Suryanarayana, Srividya, Jenna L. Wang, Mark Richter, Yuequan Shen, Wei-Jen Tang, Gerald H. Lushington, and Roland Seifert. "Distinct Interactions of 2â ²- and 3â ²-O-(N-methyl)anthraniloyl-isomers of ATP and GTP with the Adenylyl Cyclase Toxin of Bacillus Anthracis, Edema Factor." Biochemical Pharmacology 78.3 (2009): 224-30. | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/22682 | |
dc.description.abstract | Anthrax disease is caused by the spore-forming bacterium, Bacillus anthracis. Bacillus anthracis produces a calmodulin-activated adenylyl cyclase (AC) toxin, edema factor (EF). Through excessive cAMP accumulation EF disrupts host defence. In a recent study we showed that various 2′(3′)-O-N-(methyl)anthraniloyl (MANT)-substituted nucleoside 5′-triphosphates are potent inhibitors (Ki values in the 0.1-5 μM 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. Ki values of MANT-nucleotides for inhibition of catalysis correlated with Kd 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. | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
dc.subject | Edema factor | en_US |
dc.subject | Calmodulin | en_US |
dc.subject | MANT-nucleotide | en_US |
dc.subject | Fluorescence spectroscopy | en_US |
dc.subject | Molecular modelling | en_US |
dc.title | Distinct Interactions of 2′- and 3′-O-(N-Methyl)anthraniloyl-Isomers of ATP and GTP with the Adenylyl Cyclase Toxin of Bacillus anthracis, Edema Factor | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Richter, Mark | |
kusw.kudepartment | Molecular Biosciences | en_US |
dc.identifier.doi | 10.1016/j.bcp.2009.04.006 | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |
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