Cargando…
Structure Modeling of the Norepinephrine Transporter
The norepinephrine transporter (NET) is one of the monoamine transporters. Its X-ray crystal structure has not been obtained yet. Inhibitors of human NET (hNET) play a major role in the treatment of many central and peripheral nervous system diseases. In this study, we focused on the spatial structu...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022499/ https://www.ncbi.nlm.nih.gov/pubmed/31936154 http://dx.doi.org/10.3390/biom10010102 |
_version_ | 1783498029191397376 |
---|---|
author | Góral, Izabella Łątka, Kamil Bajda, Marek |
author_facet | Góral, Izabella Łątka, Kamil Bajda, Marek |
author_sort | Góral, Izabella |
collection | PubMed |
description | The norepinephrine transporter (NET) is one of the monoamine transporters. Its X-ray crystal structure has not been obtained yet. Inhibitors of human NET (hNET) play a major role in the treatment of many central and peripheral nervous system diseases. In this study, we focused on the spatial structure of a NET constructed by homology modeling on Drosophila melanogaster dopamine transporter templates. We further examined molecular construction of primary binding pocket (S1) together with secondary binding site (S2) and extracellular loop 4 (EL4). The next stage involved docking of transporter inhibitors: Reboxetine, duloxetine, desipramine, and other commonly used drugs. The procedure revealed the molecular orientation of residues and disclosed ones that are the most important for ligand binding: Phenylalanine F72, aspartic acid D75, tyrosine Y152, and phenylalanine F317. Aspartic acid D75 plays a key role in recognition of the basic amino group present in monoamine transporter inhibitors and substrates. The study also presents a comparison of hNET models with other related proteins, which could provide new insights into their interaction with therapeutics and aid future development of novel bioactive compounds. |
format | Online Article Text |
id | pubmed-7022499 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70224992020-03-09 Structure Modeling of the Norepinephrine Transporter Góral, Izabella Łątka, Kamil Bajda, Marek Biomolecules Article The norepinephrine transporter (NET) is one of the monoamine transporters. Its X-ray crystal structure has not been obtained yet. Inhibitors of human NET (hNET) play a major role in the treatment of many central and peripheral nervous system diseases. In this study, we focused on the spatial structure of a NET constructed by homology modeling on Drosophila melanogaster dopamine transporter templates. We further examined molecular construction of primary binding pocket (S1) together with secondary binding site (S2) and extracellular loop 4 (EL4). The next stage involved docking of transporter inhibitors: Reboxetine, duloxetine, desipramine, and other commonly used drugs. The procedure revealed the molecular orientation of residues and disclosed ones that are the most important for ligand binding: Phenylalanine F72, aspartic acid D75, tyrosine Y152, and phenylalanine F317. Aspartic acid D75 plays a key role in recognition of the basic amino group present in monoamine transporter inhibitors and substrates. The study also presents a comparison of hNET models with other related proteins, which could provide new insights into their interaction with therapeutics and aid future development of novel bioactive compounds. MDPI 2020-01-07 /pmc/articles/PMC7022499/ /pubmed/31936154 http://dx.doi.org/10.3390/biom10010102 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 Góral, Izabella Łątka, Kamil Bajda, Marek Structure Modeling of the Norepinephrine Transporter |
title | Structure Modeling of the Norepinephrine Transporter |
title_full | Structure Modeling of the Norepinephrine Transporter |
title_fullStr | Structure Modeling of the Norepinephrine Transporter |
title_full_unstemmed | Structure Modeling of the Norepinephrine Transporter |
title_short | Structure Modeling of the Norepinephrine Transporter |
title_sort | structure modeling of the norepinephrine transporter |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022499/ https://www.ncbi.nlm.nih.gov/pubmed/31936154 http://dx.doi.org/10.3390/biom10010102 |
work_keys_str_mv | AT goralizabella structuremodelingofthenorepinephrinetransporter AT łatkakamil structuremodelingofthenorepinephrinetransporter AT bajdamarek structuremodelingofthenorepinephrinetransporter |