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Folding correction of ABC‐transporter ABCB1 by pharmacological chaperones: a mechanistic concept
Point mutations of ATP‐binding cassette (ABC) proteins are a common cause of human diseases. Available crystal structures indicate a similarity in the architecture of several members of this protein family. Their molecular architecture makes these proteins vulnerable to mutation, when critical struc...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464349/ https://www.ncbi.nlm.nih.gov/pubmed/28603639 http://dx.doi.org/10.1002/prp2.325 |
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author | Spork, Matthias Sohail, Muhammad Imran Schmid, Diethart Ecker, Gerhard F. Freissmuth, Michael Chiba, Peter Stockner, Thomas |
author_facet | Spork, Matthias Sohail, Muhammad Imran Schmid, Diethart Ecker, Gerhard F. Freissmuth, Michael Chiba, Peter Stockner, Thomas |
author_sort | Spork, Matthias |
collection | PubMed |
description | Point mutations of ATP‐binding cassette (ABC) proteins are a common cause of human diseases. Available crystal structures indicate a similarity in the architecture of several members of this protein family. Their molecular architecture makes these proteins vulnerable to mutation, when critical structural elements are affected. The latter preferentially involve the two transmembrane domain (TMD)/nucleotide‐binding domain (NBD) interfaces (transmission interfaces), formation of which requires engagement of coupling helices of intracellular loops with NBDs. Both, formation of the active sites and engagement of the coupling helices, are contingent on correct positioning of ICLs 2 and 4 and thus an important prerequisite for proper folding. Here, we show that active site compounds are capable of rescuing P‐glycoprotein (P‐gp) mutants ∆Y490 and ∆Y1133 in a concentration‐dependent manner. These trafficking deficient mutations are located at the transmission interface in pseudosymmetric position to each other. In addition, the ability of propafenone analogs to correct folding correlates with their ability to inhibit transport of model substrates. This finding indicates that folding correction and transport inhibition by propafenone analogs are brought about by binding to the active sites. Furthermore, this study demonstrates an asymmetry in folding correction with cis‐flupentixol, which reflects the asymmetric binding properties of this modulator to P‐gp. Our results suggest a mechanistic model for corrector action in a model ABC transporter based on insights into the molecular architecture of these transporters. |
format | Online Article Text |
id | pubmed-5464349 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54643492017-06-09 Folding correction of ABC‐transporter ABCB1 by pharmacological chaperones: a mechanistic concept Spork, Matthias Sohail, Muhammad Imran Schmid, Diethart Ecker, Gerhard F. Freissmuth, Michael Chiba, Peter Stockner, Thomas Pharmacol Res Perspect Original Articles Point mutations of ATP‐binding cassette (ABC) proteins are a common cause of human diseases. Available crystal structures indicate a similarity in the architecture of several members of this protein family. Their molecular architecture makes these proteins vulnerable to mutation, when critical structural elements are affected. The latter preferentially involve the two transmembrane domain (TMD)/nucleotide‐binding domain (NBD) interfaces (transmission interfaces), formation of which requires engagement of coupling helices of intracellular loops with NBDs. Both, formation of the active sites and engagement of the coupling helices, are contingent on correct positioning of ICLs 2 and 4 and thus an important prerequisite for proper folding. Here, we show that active site compounds are capable of rescuing P‐glycoprotein (P‐gp) mutants ∆Y490 and ∆Y1133 in a concentration‐dependent manner. These trafficking deficient mutations are located at the transmission interface in pseudosymmetric position to each other. In addition, the ability of propafenone analogs to correct folding correlates with their ability to inhibit transport of model substrates. This finding indicates that folding correction and transport inhibition by propafenone analogs are brought about by binding to the active sites. Furthermore, this study demonstrates an asymmetry in folding correction with cis‐flupentixol, which reflects the asymmetric binding properties of this modulator to P‐gp. Our results suggest a mechanistic model for corrector action in a model ABC transporter based on insights into the molecular architecture of these transporters. John Wiley and Sons Inc. 2017-05-26 /pmc/articles/PMC5464349/ /pubmed/28603639 http://dx.doi.org/10.1002/prp2.325 Text en © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Spork, Matthias Sohail, Muhammad Imran Schmid, Diethart Ecker, Gerhard F. Freissmuth, Michael Chiba, Peter Stockner, Thomas Folding correction of ABC‐transporter ABCB1 by pharmacological chaperones: a mechanistic concept |
title | Folding correction of ABC‐transporter ABCB1 by pharmacological chaperones: a mechanistic concept |
title_full | Folding correction of ABC‐transporter ABCB1 by pharmacological chaperones: a mechanistic concept |
title_fullStr | Folding correction of ABC‐transporter ABCB1 by pharmacological chaperones: a mechanistic concept |
title_full_unstemmed | Folding correction of ABC‐transporter ABCB1 by pharmacological chaperones: a mechanistic concept |
title_short | Folding correction of ABC‐transporter ABCB1 by pharmacological chaperones: a mechanistic concept |
title_sort | folding correction of abc‐transporter abcb1 by pharmacological chaperones: a mechanistic concept |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464349/ https://www.ncbi.nlm.nih.gov/pubmed/28603639 http://dx.doi.org/10.1002/prp2.325 |
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