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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...

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Autores principales: Spork, Matthias, Sohail, Muhammad Imran, Schmid, Diethart, Ecker, Gerhard F., Freissmuth, Michael, Chiba, Peter, Stockner, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
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.
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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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