relation: http://publicatio.bibl.u-szeged.hu/10460/
title: An engineered scorpion toxin analogue with improved Kv1.3 selectivity displays reduced conformational flexibility
creator:  Bartók Ádám
creator:  Fehér Krisztina
creator:  Bodor Andrea
creator:  Rákosi Kinga
creator:  Tóth Gábor
creator:  Kövér Katalin E.
creator:  Panyi György
creator:  Varga Zoltán
description: The voltage-gated Kv1.3 K(+) channel plays a key role in the activation of T lymphocytes. Kv1.3 blockers selectively suppress immune responses mediated by effector memory T cells, which indicates the great potential of selective Kv1.3 inhibitors in the therapy of certain autoimmune diseases. Anuroctoxin (AnTx), a 35-amino-acid scorpion toxin is a high affinity blocker of Kv1.3, but also blocks Kv1.2 with similar potency. We designed and produced three AnTx variants: ([F32T]-AnTx, [N17A]-AnTx, [N17A/F32T]-AnTx) using solid-phase synthesis with the goal of improving the selectivity of the toxin for Kv1.3 over Kv1.2 while keeping the high affinity for Kv1.3. We used the patch-clamp technique to determine the blocking potency of the synthetic toxins on hKv1.3, mKv1.1, hKv1.2 and hKCa3.1 channels. Of the three variants [N17A/F32T]-AnTx maintained the high affinity of  the natural peptide for Kv1.3 but became more than 16000-fold selective over Kv1.2. NMR data and molecular dynamics simulations suggest that the more rigid structure with restricted conformational space of the double substituted toxin compared to the flexible wild-type one is an important determinant of toxin selectivity. Our results provide the foundation for the possibility of the production and future therapeutic application of additional, even more selective  toxins targeting various ion channels.
publisher: Nature Publishing Group
date: 2015
type: Folyóiratcikk
type: PeerReviewed
format: text
identifier: http://publicatio.bibl.u-szeged.hu/10460/1/srep18397.pdf
identifier:     Bartók Ádám;  Fehér Krisztina;  Bodor Andrea;  Rákosi Kinga;  Tóth Gábor;  Kövér Katalin E.;  Panyi György;  Varga Zoltán: An engineered scorpion toxin analogue with improved Kv1.3 selectivity displays reduced conformational flexibility.   SCIENTIFIC REPORTS, 5.  Terjedelem: 13 p.-Azonosító: 18397.  ISSN 2045-2322 (2015)     
identifier: doi:10.1038/srep18397
relation: 2989144
language: eng
relation: info:eu-repo/semantics/altIdentifier/doi/10.1038/srep18397
rights: info:eu-repo/semantics/openAccess