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An Energetically Favorable Ligand Entrance Gate of a Multidrug Transporter Revealed by Partial Nudged Elastic Band Simulations

P-glycoprotein (P-gp) is a multidrug transporter, which harnesses the chemical energy of ATP to power the efflux of diverse chemotherapeutics out of cells and thus contributes to the development of multidrug resistance (MDR) in cancer. It has been proved that the ligand-binding pocket of P-gp is loc...

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Autores principales: Xing, Juan, Mei, Hu, Huang, ShuHeng, Zhang, Duo, Pan, XianChao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406077/
https://www.ncbi.nlm.nih.gov/pubmed/30899446
http://dx.doi.org/10.1016/j.csbj.2019.02.008
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author Xing, Juan
Mei, Hu
Huang, ShuHeng
Zhang, Duo
Pan, XianChao
author_facet Xing, Juan
Mei, Hu
Huang, ShuHeng
Zhang, Duo
Pan, XianChao
author_sort Xing, Juan
collection PubMed
description P-glycoprotein (P-gp) is a multidrug transporter, which harnesses the chemical energy of ATP to power the efflux of diverse chemotherapeutics out of cells and thus contributes to the development of multidrug resistance (MDR) in cancer. It has been proved that the ligand-binding pocket of P-gp is located at the transmembrane domains (TMDs). However, the access of ligands into the binding pocket remains to be elucidated, which definitely hinder the development of P-gp inhibitors. Herein, the access pathways of a well-known substrate rhodamine-123 and a cyclopeptide inhibitor QZ-Leu were characterized by time-independent partial nudged elastic band (PNEB) simulations. The decreasing free energies along the PNEB-optimized access pathway indicated that TM4/6 cleft may be an energetically favorable entrance gate for ligand entry into the binding pocket of P-gp. The results can be reconciled with a range of experimental studies, further corroborating the reliability of the gate revealed by computational simulations. Our atomic level description of the ligand access pathway provides valuable insights into the gating mechanism for drug uptake and transport by P-gp and other multidrug transporters.
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spelling pubmed-64060772019-03-21 An Energetically Favorable Ligand Entrance Gate of a Multidrug Transporter Revealed by Partial Nudged Elastic Band Simulations Xing, Juan Mei, Hu Huang, ShuHeng Zhang, Duo Pan, XianChao Comput Struct Biotechnol J Short Communication P-glycoprotein (P-gp) is a multidrug transporter, which harnesses the chemical energy of ATP to power the efflux of diverse chemotherapeutics out of cells and thus contributes to the development of multidrug resistance (MDR) in cancer. It has been proved that the ligand-binding pocket of P-gp is located at the transmembrane domains (TMDs). However, the access of ligands into the binding pocket remains to be elucidated, which definitely hinder the development of P-gp inhibitors. Herein, the access pathways of a well-known substrate rhodamine-123 and a cyclopeptide inhibitor QZ-Leu were characterized by time-independent partial nudged elastic band (PNEB) simulations. The decreasing free energies along the PNEB-optimized access pathway indicated that TM4/6 cleft may be an energetically favorable entrance gate for ligand entry into the binding pocket of P-gp. The results can be reconciled with a range of experimental studies, further corroborating the reliability of the gate revealed by computational simulations. Our atomic level description of the ligand access pathway provides valuable insights into the gating mechanism for drug uptake and transport by P-gp and other multidrug transporters. Research Network of Computational and Structural Biotechnology 2019-02-22 /pmc/articles/PMC6406077/ /pubmed/30899446 http://dx.doi.org/10.1016/j.csbj.2019.02.008 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Short Communication
Xing, Juan
Mei, Hu
Huang, ShuHeng
Zhang, Duo
Pan, XianChao
An Energetically Favorable Ligand Entrance Gate of a Multidrug Transporter Revealed by Partial Nudged Elastic Band Simulations
title An Energetically Favorable Ligand Entrance Gate of a Multidrug Transporter Revealed by Partial Nudged Elastic Band Simulations
title_full An Energetically Favorable Ligand Entrance Gate of a Multidrug Transporter Revealed by Partial Nudged Elastic Band Simulations
title_fullStr An Energetically Favorable Ligand Entrance Gate of a Multidrug Transporter Revealed by Partial Nudged Elastic Band Simulations
title_full_unstemmed An Energetically Favorable Ligand Entrance Gate of a Multidrug Transporter Revealed by Partial Nudged Elastic Band Simulations
title_short An Energetically Favorable Ligand Entrance Gate of a Multidrug Transporter Revealed by Partial Nudged Elastic Band Simulations
title_sort energetically favorable ligand entrance gate of a multidrug transporter revealed by partial nudged elastic band simulations
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406077/
https://www.ncbi.nlm.nih.gov/pubmed/30899446
http://dx.doi.org/10.1016/j.csbj.2019.02.008
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