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

Autores
Boron, Carlos Ignacio; Bustamante, Juan Pablo; Davidge, Kelly S.; Singh, Sandip; Bowman, Lesley A.H.; Tinajero Trejo, Mariana; Carballal, Sebastián; Radi, Rafael; Poole, Robert K.; Dikshit, Kanak; Estrin, Dario Ariel; Marti, Marcelo Adrian; Boechi, Leonardo
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Boron, Carlos Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Bustamante, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Davidge, Kelly S.. The University of Nottingham; Reino Unido
Fil: Singh, Sandip. Institute of Microbial Technology; India
Fil: Bowman, Lesley A.H.. University of Oxford; Reino Unido
Fil: Tinajero Trejo, Mariana. The University of Sheffield; Reino Unido
Fil: Carballal, Sebastián. Universidad de la República; Uruguay
Fil: Radi, Rafael. Universidad de la República; Uruguay
Fil: Poole, Robert K.. The University of Sheffield; Reino Unido
Fil: Dikshit, Kanak. Institute of Microbial Technology; India
Fil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Boechi, Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina
Materia
LIGAND UPTAKE
MYCOBACTERIUM TUBERCULOSIS
TRUNCATED HEMOGLOBINS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/58903
Acceder
id CONICETDig_cebee646406cae825130a63da495e511
oai_identifier_str oai:ri.conicet.gov.ar:11336/58903
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water moleculesBoron, Carlos IgnacioBustamante, Juan PabloDavidge, Kelly S.Singh, SandipBowman, Lesley A.H.Tinajero Trejo, MarianaCarballal, SebastiánRadi, RafaelPoole, Robert K.Dikshit, KanakEstrin, Dario ArielMarti, Marcelo AdrianBoechi, LeonardoLIGAND UPTAKEMYCOBACTERIUM TUBERCULOSISTRUNCATED HEMOGLOBINShttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Mycobacterium 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.Fil: Boron, Carlos Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Bustamante, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Davidge, Kelly S.. The University of Nottingham; Reino UnidoFil: Singh, Sandip. Institute of Microbial Technology; IndiaFil: Bowman, Lesley A.H.. University of Oxford; Reino UnidoFil: Tinajero Trejo, Mariana. The University of Sheffield; Reino UnidoFil: Carballal, Sebastián. Universidad de la República; UruguayFil: Radi, Rafael. Universidad de la República; UruguayFil: Poole, Robert K.. The University of Sheffield; Reino UnidoFil: Dikshit, Kanak. Institute of Microbial Technology; IndiaFil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Boechi, Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; ArgentinaFaculty of 1000 Ltd2015-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/58903Boron, Carlos Ignacio; Bustamante, Juan Pablo; Davidge, Kelly S.; Singh, Sandip; Bowman, Lesley A.H.; et al.; Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules; Faculty of 1000 Ltd; F1000Research; 4; 2-2015; 1-121759-796XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.12688/f1000research.5921.2info:eu-repo/semantics/altIdentifier/url/https://f1000research.com/articles/4-22/v2info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:52:17Zoai:ri.conicet.gov.ar:11336/58903instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:52:17.661CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv 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
spellingShingle Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules
Boron, Carlos Ignacio
LIGAND UPTAKE
MYCOBACTERIUM TUBERCULOSIS
TRUNCATED HEMOGLOBINS
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
dc.creator.none.fl_str_mv Boron, Carlos Ignacio
Bustamante, Juan Pablo
Davidge, Kelly S.
Singh, Sandip
Bowman, Lesley A.H.
Tinajero Trejo, Mariana
Carballal, Sebastián
Radi, Rafael
Poole, Robert K.
Dikshit, Kanak
Estrin, Dario Ariel
Marti, Marcelo Adrian
Boechi, Leonardo
author Boron, Carlos Ignacio
author_facet Boron, Carlos Ignacio
Bustamante, Juan Pablo
Davidge, Kelly S.
Singh, Sandip
Bowman, Lesley A.H.
Tinajero Trejo, Mariana
Carballal, Sebastián
Radi, Rafael
Poole, Robert K.
Dikshit, Kanak
Estrin, Dario Ariel
Marti, Marcelo Adrian
Boechi, Leonardo
author_role author
author2 Bustamante, Juan Pablo
Davidge, Kelly S.
Singh, Sandip
Bowman, Lesley A.H.
Tinajero Trejo, Mariana
Carballal, Sebastián
Radi, Rafael
Poole, Robert K.
Dikshit, Kanak
Estrin, Dario Ariel
Marti, Marcelo Adrian
Boechi, Leonardo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv LIGAND UPTAKE
MYCOBACTERIUM TUBERCULOSIS
TRUNCATED HEMOGLOBINS
topic LIGAND UPTAKE
MYCOBACTERIUM TUBERCULOSIS
TRUNCATED HEMOGLOBINS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Boron, Carlos Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Bustamante, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Davidge, Kelly S.. The University of Nottingham; Reino Unido
Fil: Singh, Sandip. Institute of Microbial Technology; India
Fil: Bowman, Lesley A.H.. University of Oxford; Reino Unido
Fil: Tinajero Trejo, Mariana. The University of Sheffield; Reino Unido
Fil: Carballal, Sebastián. Universidad de la República; Uruguay
Fil: Radi, Rafael. Universidad de la República; Uruguay
Fil: Poole, Robert K.. The University of Sheffield; Reino Unido
Fil: Dikshit, Kanak. Institute of Microbial Technology; India
Fil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Boechi, Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina
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.
publishDate 2015
dc.date.none.fl_str_mv 2015-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/58903
Boron, Carlos Ignacio; Bustamante, Juan Pablo; Davidge, Kelly S.; Singh, Sandip; Bowman, Lesley A.H.; et al.; Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules; Faculty of 1000 Ltd; F1000Research; 4; 2-2015; 1-12
1759-796X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/58903
identifier_str_mv Boron, Carlos Ignacio; Bustamante, Juan Pablo; Davidge, Kelly S.; Singh, Sandip; Bowman, Lesley A.H.; et al.; Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules; Faculty of 1000 Ltd; F1000Research; 4; 2-2015; 1-12
1759-796X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.12688/f1000research.5921.2
info:eu-repo/semantics/altIdentifier/url/https://f1000research.com/articles/4-22/v2
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Faculty of 1000 Ltd
publisher.none.fl_str_mv Faculty of 1000 Ltd
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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