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Equilibrated Atomic Models of Outward-Facing P-glycoprotein and Effect of ATP Binding on Structural Dynamics

P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that alternates between inward- and outward-facing conformations to capture and force substrates out of cells like a peristaltic pump. The high degree of similarity in outward-facing structures across evolution of ABC transporters all...

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Autores principales: Pan, Lurong, Aller, Stephen G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389535/
https://www.ncbi.nlm.nih.gov/pubmed/25600711
http://dx.doi.org/10.1038/srep07880
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author Pan, Lurong
Aller, Stephen G.
author_facet Pan, Lurong
Aller, Stephen G.
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description P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that alternates between inward- and outward-facing conformations to capture and force substrates out of cells like a peristaltic pump. The high degree of similarity in outward-facing structures across evolution of ABC transporters allowed construction of a high-confidence outward-facing Pgp atomic model based on crystal structures of outward-facing Sav1866 and inward-facing Pgp. The model adhered to previous experimentally determined secondary- and tertiary- configurations during all-atom molecular dynamics simulations in the presence or absence of MgATP. Three long lasting (>100 ns) meta-stable states were apparent in the presence of MgATP revealing new insights into alternating access. The two ATP-binding pockets are highly asymmetric resulting in differential control of overall structural dynamics and allosteric regulation of the drug-binding pocket. Equilibrated Pgp has a considerably different electrostatic profile compared to Sav1866 that implicates significant kinetic and thermodynamic differences in transport mechanisms.
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spelling pubmed-43895352015-04-08 Equilibrated Atomic Models of Outward-Facing P-glycoprotein and Effect of ATP Binding on Structural Dynamics Pan, Lurong Aller, Stephen G. Sci Rep Article P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that alternates between inward- and outward-facing conformations to capture and force substrates out of cells like a peristaltic pump. The high degree of similarity in outward-facing structures across evolution of ABC transporters allowed construction of a high-confidence outward-facing Pgp atomic model based on crystal structures of outward-facing Sav1866 and inward-facing Pgp. The model adhered to previous experimentally determined secondary- and tertiary- configurations during all-atom molecular dynamics simulations in the presence or absence of MgATP. Three long lasting (>100 ns) meta-stable states were apparent in the presence of MgATP revealing new insights into alternating access. The two ATP-binding pockets are highly asymmetric resulting in differential control of overall structural dynamics and allosteric regulation of the drug-binding pocket. Equilibrated Pgp has a considerably different electrostatic profile compared to Sav1866 that implicates significant kinetic and thermodynamic differences in transport mechanisms. Nature Publishing Group 2015-01-20 /pmc/articles/PMC4389535/ /pubmed/25600711 http://dx.doi.org/10.1038/srep07880 Text en Copyright © 2015, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Article
Pan, Lurong
Aller, Stephen G.
Equilibrated Atomic Models of Outward-Facing P-glycoprotein and Effect of ATP Binding on Structural Dynamics
title Equilibrated Atomic Models of Outward-Facing P-glycoprotein and Effect of ATP Binding on Structural Dynamics
title_full Equilibrated Atomic Models of Outward-Facing P-glycoprotein and Effect of ATP Binding on Structural Dynamics
title_fullStr Equilibrated Atomic Models of Outward-Facing P-glycoprotein and Effect of ATP Binding on Structural Dynamics
title_full_unstemmed Equilibrated Atomic Models of Outward-Facing P-glycoprotein and Effect of ATP Binding on Structural Dynamics
title_short Equilibrated Atomic Models of Outward-Facing P-glycoprotein and Effect of ATP Binding on Structural Dynamics
title_sort equilibrated atomic models of outward-facing p-glycoprotein and effect of atp binding on structural dynamics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389535/
https://www.ncbi.nlm.nih.gov/pubmed/25600711
http://dx.doi.org/10.1038/srep07880
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