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001-es BibID:BIBFORM079020
035-os BibID:(absztrakt azonosító)1849-Plat (WoS)000430450000363
Első szerző:Karbat, Izhar
Cím:An Allosteric Action Mechanism of a K+ Pore Blocker Revealed at the Atomic Level / Izhar Karbat, Hagit Altman-Gueta, G. Tibor Szántó, Shelly Hamer-Rogotner, Orly Dym, Felix Frolow, Dalia Gordon, Gyorgy Panyi, Michael Gurevitz, Eitan Reuveny
Dátum:2018
ISSN:0006-3495
Megjegyzések:Voltage gated ion channels gate in response to changes in the electrical membrane potential by the coupling of a voltage sensing module with an ion-selective pore. Toxins that target these channels are traditionally classified as either pore-blockers or gating-modifiers, the former bind and physically occlude the channel pore, while the later bind the voltage sensing module and restrict its movement in response to alterations in the membrane potential. Here we present Cs1, a kunitz-fold cone-snail toxin that blocks the Drosophila Shaker isoform with high affinity and seem to defy the traditional classification. We first obtained high resolution crystal structures of Cs1 and several of its mutants. Then, using site directed mutagenesis followed by double-mutant cycle analysis we identified key residue pairs in contact at the toxin-channel interface, which was clearly confined to the channel pore-module. Unconstrained rigid docking followed by a whole-atom molecular dynamics simulations yielded a model that was consistent with the experimental results, in which the toxin was bound off the pore axis and allowed the access of water molecules to the pore. Electrophysiological assays established that Cs1 does not dissociate from its binding site upon depolarization, and that its affinity for the channel is independent of the external K+ concentration, further setting it apart from the classical pore-blockers. Analysis of our MD simulations suggest that Cs1 blocks ion conductance using a novel allosteric mechanism that directly involves structural water molecules buried behind the selectivity filter of the channel.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idézhető absztrakt
folyóiratcikk
Megjelenés:Biophysical Journal. - 114 : 3 (2018), p. 375a. -
További szerzők:Altman-Gueta, Hagit Szántó Gábor Tibor (1980-) (vegyész) Hamer-Rogotner, Shelly Dym, Orly Frolow, Felix Gordon, Dalia Panyi György (1966-) (biofizikus) Gurevitz, Michael Reuveny, Eitan
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