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 pos...

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Main Authors:	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
Format:	Online
Language:	English
Published:	F1000Research 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591903/

id	pubmed-4591903
recordtype	oai_dc
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 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.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
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
spellingShingle	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
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
title	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_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_sort	ligand uptake in mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules
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.
publisher	F1000Research
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591903/
_version_	1613483080174010368

Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules

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