Nanomechanics combined with HDX reveals allosteric drug binding sites of CFTR NBD1

Padányi, Rita [Padányi, Rita (Molekuláris biológia), szerző] Biofizikai és Sugárbiológiai Intézet (SE / AOK / I); Farkas, Bianka* [Farkas, Bianka Vivien (Biológia tudomány...), szerző] Biofizikai és Sugárbiológiai Intézet (SE / AOK / I); Tordai, Hedvig [Tordai, Hedvig (molekuláris biológia), szerző] Biofizikai és Sugárbiológiai Intézet (SE / AOK / I); Kiss, Bálint [Kiss, Bálint (Biofizika), szerző] Biofizikai és Sugárbiológiai Intézet (SE / AOK / I); Grubmüller, Helmut; Soya, Naoto; Lukács, Gergely L.; Kellermayer, Miklós [Kellermayer, Miklós (Biofizika), szerző] Biofizikai és Sugárbiológiai Intézet (SE / AOK / I); Hegedűs, Tamás ✉ [Hegedűs, Tamás (bioinformatika, b...), szerző] Biofizikai és Sugárbiológiai Intézet (SE / AOK / I)

Angol nyelvű Szakcikk (Folyóiratcikk) Tudományos
  • SJR Scopus - Biophysics: D1
Cystic fibrosis (CF) is a frequent genetic disease in Caucasians that is caused by the deletion of F508 (DF508) in the nucleotide binding domain 1 (NBD1) of the CF transmembrane conductance regulator (CFTR). The DF508 compromises the folding energetics of the NBD1, as well as the folding of three other CFTR domains. Combination of FDA approved corrector molecules can efficiently but incompletely rescue the DF508-CFTR folding and stability defect. Thus, new pharmacophores that would reinstate the wildtype-like conformational stability of the DF508-NBD1 would be highly beneficial. The most prominent molecule, 5-bromoindole-3-acetic acid (BIA) that can thermally stabilize the NBD1 has low potency and efficacy. To gain insights into the NBD1 (un)folding dynamics and BIA binding site localization, we combined molecular dynamics (MD) simulations, atomic force spectroscopy (AFM) and hydrogendeuterium exchange (HDX) experiments. We found that the NBD1 a-subdomain with three adjacent strands from the b-subdomain plays an important role in early folding steps, when crucial non-native interactions are formed via residue F508. Our AFM and HDX experiments showed that BIA associates with this a-core region and increases the resistance of the DF508-NBD1 against mechanical unfolding, a phenomenon that could be exploited in future developments of folding correctors. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSLMásolásNyomtatás
2024-05-21 22:51