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Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules
Mycobacterium tuberculosis, the causative agent of human tuberculosis, has two proteins belonging to the truncated hemoglobin (trHb) family. Mt-trHbN presents well-defined internal hydrophobic tunnels that allow O (2) and (•)NO to migrate easily from the solvent to the active site, whereas Mt-trHbO...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
F1000Research
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591903/ https://www.ncbi.nlm.nih.gov/pubmed/26478812 http://dx.doi.org/10.12688/f1000research.5921.2 |
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author | Boron, Ignacio Bustamante, Juan Pablo Davidge, Kelly S Singh, Sandip Bowman, Lesley AH Tinajero-Trejo, Mariana Carballal, Sebastián Radi, Rafael Poole, Robert K Dikshit, Kanak Estrin, Dario A Marti, Marcelo A Boechi, Leonardo |
author_facet | Boron, Ignacio Bustamante, Juan Pablo Davidge, Kelly S Singh, Sandip Bowman, Lesley AH Tinajero-Trejo, Mariana Carballal, Sebastián Radi, Rafael Poole, Robert K Dikshit, Kanak Estrin, Dario A Marti, Marcelo A Boechi, Leonardo |
author_sort | Boron, Ignacio |
collection | PubMed |
description | Mycobacterium tuberculosis, the causative agent of human tuberculosis, has two proteins belonging to the truncated hemoglobin (trHb) family. Mt-trHbN presents well-defined internal hydrophobic tunnels that allow O (2) and (•)NO to migrate easily from the solvent to the active site, whereas Mt-trHbO possesses tunnels interrupted by a few bulky residues, particularly a tryptophan at position G8. Differential ligand migration rates allow Mt-trHbN to detoxify (•)NO, a crucial step for pathogen survival once under attack by the immune system, much more efficiently than Mt-trHbO. In order to investigate the differences between these proteins, we performed experimental kinetic measurements, (•)NO decomposition, as well as molecular dynamics simulations of the wild type Mt-trHbN and two mutants, VG8F and VG8W. These mutations affect both the tunnels accessibility as well as the affinity of distal site water molecules, thus modifying the ligand access to the iron. We found that a single mutation allows Mt-trHbN to acquire ligand migration rates comparable to those observed for Mt-trHbO, confirming that ligand migration is regulated by the internal tunnel architecture as well as by water molecules stabilized in the active site. |
format | Online Article Text |
id | pubmed-4591903 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | F1000Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-45919032015-10-15 Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules Boron, Ignacio Bustamante, Juan Pablo Davidge, Kelly S Singh, Sandip Bowman, Lesley AH Tinajero-Trejo, Mariana Carballal, Sebastián Radi, Rafael Poole, Robert K Dikshit, Kanak Estrin, Dario A Marti, Marcelo A Boechi, Leonardo F1000Res Research Article Mycobacterium tuberculosis, the causative agent of human tuberculosis, has two proteins belonging to the truncated hemoglobin (trHb) family. Mt-trHbN presents well-defined internal hydrophobic tunnels that allow O (2) and (•)NO to migrate easily from the solvent to the active site, whereas Mt-trHbO possesses tunnels interrupted by a few bulky residues, particularly a tryptophan at position G8. Differential ligand migration rates allow Mt-trHbN to detoxify (•)NO, a crucial step for pathogen survival once under attack by the immune system, much more efficiently than Mt-trHbO. In order to investigate the differences between these proteins, we performed experimental kinetic measurements, (•)NO decomposition, as well as molecular dynamics simulations of the wild type Mt-trHbN and two mutants, VG8F and VG8W. These mutations affect both the tunnels accessibility as well as the affinity of distal site water molecules, thus modifying the ligand access to the iron. We found that a single mutation allows Mt-trHbN to acquire ligand migration rates comparable to those observed for Mt-trHbO, confirming that ligand migration is regulated by the internal tunnel architecture as well as by water molecules stabilized in the active site. F1000Research 2015-07-22 /pmc/articles/PMC4591903/ /pubmed/26478812 http://dx.doi.org/10.12688/f1000research.5921.2 Text en Copyright: © 2015 Boron I et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Boron, Ignacio Bustamante, Juan Pablo Davidge, Kelly S Singh, Sandip Bowman, Lesley AH Tinajero-Trejo, Mariana Carballal, Sebastián Radi, Rafael Poole, Robert K Dikshit, Kanak Estrin, Dario A Marti, Marcelo A Boechi, Leonardo Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules |
title | Ligand uptake in
Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules |
title_full | Ligand uptake in
Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules |
title_fullStr | Ligand uptake in
Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules |
title_full_unstemmed | Ligand uptake in
Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules |
title_short | Ligand uptake in
Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules |
title_sort | ligand uptake in
mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591903/ https://www.ncbi.nlm.nih.gov/pubmed/26478812 http://dx.doi.org/10.12688/f1000research.5921.2 |
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