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

Padányi, R., Farkas, B., Tordai, H., Kiss, B., Grubmüller, H., Soya, N., et al. (2022). Nanomechanics combined with HDX reveals allosteric drug binding sites of CFTR NBD1. Comput. Struct. Biotec. J., 20, 2587-2599. doi:10.1016/j.csbj.2022.05.036.

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Padányi, R., Author
Farkas, B., Author
Tordai, H., Author
Kiss, B., Author
Grubmüller, H.1, Author           
Soya, N., Author
Lukács, GL., Author
Kellermayer, M., Author
Hegedus, T., Author
Affiliations:
1Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350132              

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Free keywords: CFTR, F508 deletion, Cystic fibrosis, Atomic force spectroscopy, Hydrogen-deuterium exchange, Molecular dynamics simulations
 Abstract: 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 wild-type-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 hydrogen-
deuterium 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.

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Language(s): eng - English
 Dates: 2022-05-172022-03-012022-05-192022-05-23
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.csbj.2022.05.036
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Project name : This work was supported by funds to T. Hegedus from the Cystic Fibrosis Foundation (CFF): HEGEDU18I0, HEGEDU20I0; and from NRDIO/NKFIH: K127961; to G. L. Lukacs from CCF LUKACS20G0, CIHR, CFI and Canada Research Chair Program to G. Lukacs.
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Title: Comput. Struct. Biotec. J.
Source Genre: Journal
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Pages: - Volume / Issue: 20 Sequence Number: - Start / End Page: 2587 - 2599 Identifier: -