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Dynamical Behavior of the Human Ferroportin Homologue from Bdellovibrio bacteriovorus: Insight into the Ligand Recognition Mechanism

Members of the major facilitator superfamily of transporters (MFS) play an essential role in many physiological processes such as development, neurotransmission, and signaling. Aberrant functions of MFS proteins are associated with several diseases, including cancer, schizophrenia, epilepsy, amyotro...

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Autores principales: Tortosa, Valentina, Bonaccorsi di Patti, Maria Carmela, Iacovelli, Federico, Pasquadibisceglie, Andrea, Falconi, Mattia, Musci, Giovanni, Polticelli, Fabio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555787/
https://www.ncbi.nlm.nih.gov/pubmed/32947891
http://dx.doi.org/10.3390/ijms21186785
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author Tortosa, Valentina
Bonaccorsi di Patti, Maria Carmela
Iacovelli, Federico
Pasquadibisceglie, Andrea
Falconi, Mattia
Musci, Giovanni
Polticelli, Fabio
author_facet Tortosa, Valentina
Bonaccorsi di Patti, Maria Carmela
Iacovelli, Federico
Pasquadibisceglie, Andrea
Falconi, Mattia
Musci, Giovanni
Polticelli, Fabio
author_sort Tortosa, Valentina
collection PubMed
description Members of the major facilitator superfamily of transporters (MFS) play an essential role in many physiological processes such as development, neurotransmission, and signaling. Aberrant functions of MFS proteins are associated with several diseases, including cancer, schizophrenia, epilepsy, amyotrophic lateral sclerosis and Alzheimer’s disease. MFS transporters are also involved in multidrug resistance in bacteria and fungi. The structures of most MFS members, especially those of members with significant physiological relevance, are yet to be solved. The lack of structural and functional information impedes our detailed understanding, and thus the pharmacological targeting, of these transporters. To improve our knowledge on the mechanistic principles governing the function of MSF members, molecular dynamics (MD) simulations were performed on the inward-facing and outward-facing crystal structures of the human ferroportin homologue from the Gram-negative bacterium Bdellovibrio bacteriovorus (BdFpn). Several simulations with an excess of iron ions were also performed to explore the relationship between the protein’s dynamics and the ligand recognition mechanism. The results reinforce the existence of the alternating-access mechanism already described for other MFS members. In addition, the reorganization of salt bridges, some of which are conserved in several MFS members, appears to be a key molecular event facilitating the conformational change of the transporter.
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spelling pubmed-75557872020-10-19 Dynamical Behavior of the Human Ferroportin Homologue from Bdellovibrio bacteriovorus: Insight into the Ligand Recognition Mechanism Tortosa, Valentina Bonaccorsi di Patti, Maria Carmela Iacovelli, Federico Pasquadibisceglie, Andrea Falconi, Mattia Musci, Giovanni Polticelli, Fabio Int J Mol Sci Article Members of the major facilitator superfamily of transporters (MFS) play an essential role in many physiological processes such as development, neurotransmission, and signaling. Aberrant functions of MFS proteins are associated with several diseases, including cancer, schizophrenia, epilepsy, amyotrophic lateral sclerosis and Alzheimer’s disease. MFS transporters are also involved in multidrug resistance in bacteria and fungi. The structures of most MFS members, especially those of members with significant physiological relevance, are yet to be solved. The lack of structural and functional information impedes our detailed understanding, and thus the pharmacological targeting, of these transporters. To improve our knowledge on the mechanistic principles governing the function of MSF members, molecular dynamics (MD) simulations were performed on the inward-facing and outward-facing crystal structures of the human ferroportin homologue from the Gram-negative bacterium Bdellovibrio bacteriovorus (BdFpn). Several simulations with an excess of iron ions were also performed to explore the relationship between the protein’s dynamics and the ligand recognition mechanism. The results reinforce the existence of the alternating-access mechanism already described for other MFS members. In addition, the reorganization of salt bridges, some of which are conserved in several MFS members, appears to be a key molecular event facilitating the conformational change of the transporter. MDPI 2020-09-16 /pmc/articles/PMC7555787/ /pubmed/32947891 http://dx.doi.org/10.3390/ijms21186785 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tortosa, Valentina
Bonaccorsi di Patti, Maria Carmela
Iacovelli, Federico
Pasquadibisceglie, Andrea
Falconi, Mattia
Musci, Giovanni
Polticelli, Fabio
Dynamical Behavior of the Human Ferroportin Homologue from Bdellovibrio bacteriovorus: Insight into the Ligand Recognition Mechanism
title Dynamical Behavior of the Human Ferroportin Homologue from Bdellovibrio bacteriovorus: Insight into the Ligand Recognition Mechanism
title_full Dynamical Behavior of the Human Ferroportin Homologue from Bdellovibrio bacteriovorus: Insight into the Ligand Recognition Mechanism
title_fullStr Dynamical Behavior of the Human Ferroportin Homologue from Bdellovibrio bacteriovorus: Insight into the Ligand Recognition Mechanism
title_full_unstemmed Dynamical Behavior of the Human Ferroportin Homologue from Bdellovibrio bacteriovorus: Insight into the Ligand Recognition Mechanism
title_short Dynamical Behavior of the Human Ferroportin Homologue from Bdellovibrio bacteriovorus: Insight into the Ligand Recognition Mechanism
title_sort dynamical behavior of the human ferroportin homologue from bdellovibrio bacteriovorus: insight into the ligand recognition mechanism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555787/
https://www.ncbi.nlm.nih.gov/pubmed/32947891
http://dx.doi.org/10.3390/ijms21186785
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