Dynamical Regulation of Ligand Migration by a Gate-Opening Molecular Switch in Truncated Hemoglobin-N fromMycobacterium tuberculosis

Axel Bidon-Chanal; Marcelo A. Martí; Darío A. Estrin; F. Javier Luque

doi:10.1021/ja0689987

Dynamical Regulation of Ligand Migration by a Gate-Opening Molecular Switch in Truncated Hemoglobin-N fromMycobacterium tuberculosis

Journal of the American Chemical Society ◽

10.1021/ja0689987 ◽

2007 ◽

Vol 129 (21) ◽

pp. 6782-6788 ◽

Cited By ~ 35

Author(s):

Axel Bidon-Chanal ◽

Marcelo A. Martí ◽

Darío A. Estrin ◽

F. Javier Luque

Keyword(s):

Molecular Switch ◽

Truncated Hemoglobin ◽

Gate Opening ◽

Ligand Migration

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Following Ligand Migration Pathways from Picoseconds to Milliseconds in Type II Truncated Hemoglobin from Thermobifida fusca

PLoS ONE ◽

10.1371/journal.pone.0039884 ◽

2012 ◽

Vol 7 (7) ◽

pp. e39884 ◽

Cited By ~ 20

Author(s):

Agnese Marcelli ◽

Stefania Abbruzzetti ◽

Juan Pablo Bustamante ◽

Alessandro Feis ◽

Alessandra Bonamore ◽

...

Keyword(s):

Thermobifida Fusca ◽

Type Ii ◽

Truncated Hemoglobin ◽

Ligand Migration ◽

Migration Pathways

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

F1000Research ◽

10.12688/f1000research.5921.1 ◽

2015 ◽

Vol 4 ◽

pp. 22 ◽

Cited By ~ 1

Author(s):

Ignacio Boron ◽

Juan Pablo Bustamante ◽

Kelly S Davidge ◽

Sandip Singh ◽

Lesley AH Bowman ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Active Site ◽

Water Molecules ◽

Single Mutation ◽

Truncated Hemoglobin ◽

Kinetic Measurements ◽

Migration Rates ◽

Ligand Migration ◽

Site Water ◽

Dynamics Simulations

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 O2 and •NO to migrate easily from the solvent to the active site, whereas Mt-trHbO possesses tunnels that are partially blocked 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 introduce modifications in both tunnel topologies and affect the incoming ligand capacity to displace retained water molecules at the active site. 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.

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Structural determinants of ligand migration in Mycobacterium tuberculosis truncated hemoglobin O

Proteins Structure Function and Bioinformatics ◽

10.1002/prot.22072 ◽

2008 ◽

Vol 73 (2) ◽

pp. 372-379 ◽

Cited By ~ 41

Author(s):

Leonardo Boechi ◽

Marcelo A. Martí ◽

Mario Milani ◽

Martino Bolognesi ◽

F. Javier Luque ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Truncated Hemoglobin ◽

Structural Determinants ◽

Ligand Migration

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Ligand migration in the truncated hemoglobin of Mycobacterium tuberculosis

IUBMB Life ◽

10.1002/iub.438 ◽

2011 ◽

Vol 63 (3) ◽

pp. 214-220 ◽

Cited By ~ 7

Author(s):

Maxime S. Heroux ◽

Anne D. Mohan ◽

Kenneth W. Olsen

Keyword(s):

Mycobacterium Tuberculosis ◽

Truncated Hemoglobin ◽

Ligand Migration

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

F1000Research ◽

10.12688/f1000research.5921.2 ◽

2015 ◽

Vol 4 ◽

pp. 22 ◽

Cited By ~ 5

Author(s):

Ignacio Boron ◽

Juan Pablo Bustamante ◽

Kelly S Davidge ◽

Sandip Singh ◽

Lesley AH Bowman ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Active Site ◽

Water Molecules ◽

Single Mutation ◽

Truncated Hemoglobin ◽

Kinetic Measurements ◽

Migration Rates ◽

Ligand Migration ◽

Site Water ◽

Dynamics Simulations

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 O2 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.

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