Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.

The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy t...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Robert Schulz, Attilio V Vargiu, Francesca Collu, Ulrich Kleinekathöfer, Paolo Ruggerone
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f09fe10093e74a379063b2e3610e2371
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f09fe10093e74a379063b2e3610e2371
record_format	dspace
spelling	oai:doaj.org-article:f09fe10093e74a379063b2e3610e23712021-12-02T19:58:22ZFunctional rotation of the transporter AcrB: insights into drug extrusion from simulations.1553-734X1553-735810.1371/journal.pcbi.1000806https://doaj.org/article/f09fe10093e74a379063b2e3610e23712010-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20548943/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-function relationship of this transporter. Our results indicate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. Furthermore, we provide strong evidence for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. A concerted opening of the channel between the binding pocket and the gate further favors the displacement of the drug. This microscopically well-funded information allows one to identify the role of specific amino acids during the transitions and to shed light on the functioning of AcrB.Robert SchulzAttilio V VargiuFrancesca ColluUlrich KleinekathöferPaolo RuggeronePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 6, Iss 6, p e1000806 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Robert Schulz Attilio V Vargiu Francesca Collu Ulrich Kleinekathöfer Paolo Ruggerone Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.
description	The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-function relationship of this transporter. Our results indicate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. Furthermore, we provide strong evidence for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. A concerted opening of the channel between the binding pocket and the gate further favors the displacement of the drug. This microscopically well-funded information allows one to identify the role of specific amino acids during the transitions and to shed light on the functioning of AcrB.
format	article
author	Robert Schulz Attilio V Vargiu Francesca Collu Ulrich Kleinekathöfer Paolo Ruggerone
author_facet	Robert Schulz Attilio V Vargiu Francesca Collu Ulrich Kleinekathöfer Paolo Ruggerone
author_sort	Robert Schulz
title	Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.
title_short	Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.
title_full	Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.
title_fullStr	Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.
title_full_unstemmed	Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.
title_sort	functional rotation of the transporter acrb: insights into drug extrusion from simulations.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/f09fe10093e74a379063b2e3610e2371
work_keys_str_mv	AT robertschulz functionalrotationofthetransporteracrbinsightsintodrugextrusionfromsimulations AT attiliovvargiu functionalrotationofthetransporteracrbinsightsintodrugextrusionfromsimulations AT francescacollu functionalrotationofthetransporteracrbinsightsintodrugextrusionfromsimulations AT ulrichkleinekathofer functionalrotationofthetransporteracrbinsightsintodrugextrusionfromsimulations AT paoloruggerone functionalrotationofthetransporteracrbinsightsintodrugextrusionfromsimulations
_version_	1718375814724059136

Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.

Ejemplares similares