Blockage of anthrax PA63 pore by a multicharged high-affinity toxin inhibitor.

Biophysical Journal
Ekaterina M NestorovichSergey M Bezrukov

Abstract

Single channels of Bacillus anthracis protective antigen, PA(63), were reconstituted into planar lipid membranes and their inhibition by cationic aminopropylthio-beta-cyclodextrin, AmPrbetaCD, was studied. The design of the highly efficient inhibitor, the sevenfold symmetrical cyclodextrin molecule chemically modified to add seven positive charges, was guided by the symmetry and predominantly negative charge of the PA(63) pore. The protective action of this compound has been demonstrated earlier at both single-molecule and whole-organism levels. In this study, using noise analysis, statistics of time-resolved single-channel closure events, and multichannel measurements, we find that AmPrbetaCD action is bimodal. The inhibitor, when added to the cis side of the membrane, blocks the channel reversibly. At high salt concentrations, the AmPrbetaCD blockage of the channel is well described as a two-state Markov process, in which both the on- and off-rates are functions of the salt concentration, whereas the applied voltage affects only the off-rate. At salt concentrations smaller than 1.5 M, the second mode of AmPrbetaCD action on the channel is discovered: addition of the inhibitor enhances voltage gating, making the closed states ...Continue Reading

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Citations

Oct 13, 2012·Chemical Reviews·Ekaterina M Nestorovich, Sergey M Bezrukov
Nov 20, 2012·Chemical Reviews·Joseph E ReinerJohn J Kasianowicz
Sep 8, 2012·Journal of Medicinal Chemistry·Alexander N WeinMichael Peredelchuk
Oct 27, 2012·Proceedings of the National Academy of Sciences of the United States of America·Ekaterina M NestorovichSergey M Bezrukov
May 11, 2011·Antimicrobial Agents and Chemotherapy·Konstantina YannakopoulouVladimir A Karginov
Sep 13, 2013·Annual Review of Microbiology·Anne H Delcour
Aug 26, 2014·Toxins·Philip A Gurnev, Ekaterina M Nestorovich
Jan 23, 2014·Expert Opinion on Drug Discovery·Ekaterina M Nestorovich, Sergey M Bezrukov
Dec 15, 2015·Pathogens and Disease·Sergey M Bezrukov, Ekaterina M Nestorovich
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Jul 24, 2013·Biophysical Chemistry·Marta MarchiorettoGregor Anderluh
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Mar 17, 2017·Proceedings of the National Academy of Sciences of the United States of America·Goli Yamini, Ekaterina M Nestorovich
Oct 8, 2019·Biophysical Journal·Sanaz Momben AbolfathEkaterina M Nestorovich
May 21, 2021·The Journal of Physical Chemistry. B·Goli YaminiEkaterina M Nestorovich
Apr 30, 2020·Biophysical Journal·Jayesh A BafnaM Alphan Aksoyoglu
Aug 2, 2021·Biochimica Et Biophysica Acta. Biomembranes·Wenxing Liu, Ekaterina M Nestorovich
Jul 19, 2021·Proteomics·Jiaxin SunLiviu Movileanu
Jun 24, 2014·Biomacromolecules·Philip FörstnerHolger Barth

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