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 poss...
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2015
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_20461402_v4_n_p_Boechi http://hdl.handle.net/20.500.12110/paper_20461402_v4_n_p_Boechi |
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paper:paper_20461402_v4_n_p_Boechi2023-06-08T16:33:43Z Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules Boechi, Leonardo Bustamante, Juan Pablo Estrin, Dario Ariel Martí, Marcelo Adrián carbon monoxide nitric oxide truncated hemoglobin active site water molecule Article bacterial kinetics computer model controlled study decomposition internal tunnel molecular dynamics molecule mutant mutation Mycobacterium tuberculosis protein structure wild type 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. © 2015. Fil:Boechi, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Bustamante, J.P. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Marti, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_20461402_v4_n_p_Boechi http://hdl.handle.net/20.500.12110/paper_20461402_v4_n_p_Boechi |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
carbon monoxide nitric oxide truncated hemoglobin active site water molecule Article bacterial kinetics computer model controlled study decomposition internal tunnel molecular dynamics molecule mutant mutation Mycobacterium tuberculosis protein structure wild type |
| spellingShingle |
carbon monoxide nitric oxide truncated hemoglobin active site water molecule Article bacterial kinetics computer model controlled study decomposition internal tunnel molecular dynamics molecule mutant mutation Mycobacterium tuberculosis protein structure wild type Boechi, Leonardo Bustamante, Juan Pablo Estrin, Dario Ariel Martí, Marcelo Adrián Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules |
| topic_facet |
carbon monoxide nitric oxide truncated hemoglobin active site water molecule Article bacterial kinetics computer model controlled study decomposition internal tunnel molecular dynamics molecule mutant mutation Mycobacterium tuberculosis protein structure wild type |
| 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. © 2015. |
| author |
Boechi, Leonardo Bustamante, Juan Pablo Estrin, Dario Ariel Martí, Marcelo Adrián |
| author_facet |
Boechi, Leonardo Bustamante, Juan Pablo Estrin, Dario Ariel Martí, Marcelo Adrián |
| author_sort |
Boechi, Leonardo |
| 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 |
| publishDate |
2015 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_20461402_v4_n_p_Boechi http://hdl.handle.net/20.500.12110/paper_20461402_v4_n_p_Boechi |
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1768542103307026432 |