Role of PheE15 gate in ligand entry and nitric oxide detoxification function of mycobacterium tuberculosis truncated hemoglobin N.

The truncated hemoglobin N, HbN, of Mycobacterium tuberculosis is endowed with a potent nitric oxide dioxygenase (NOD) activity that allows it to relieve nitrosative stress and enhance in vivo survival of its host. Despite its small size, the protein matrix of HbN hosts a two-branched tunnel, consis...

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Autores principales:	Ana Oliveira, Sandeep Singh, Axel Bidon-Chanal, Flavio Forti, Marcelo A Martí, Leonardo Boechi, Dario A Estrin, Kanak L Dikshit, F Javier Luque
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d4fa0b2d6d6c4787a9cfc4e8faf134e9
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spelling	oai:doaj.org-article:d4fa0b2d6d6c4787a9cfc4e8faf134e92021-11-18T08:09:19ZRole of PheE15 gate in ligand entry and nitric oxide detoxification function of mycobacterium tuberculosis truncated hemoglobin N.1932-620310.1371/journal.pone.0049291https://doaj.org/article/d4fa0b2d6d6c4787a9cfc4e8faf134e92012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23145144/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The truncated hemoglobin N, HbN, of Mycobacterium tuberculosis is endowed with a potent nitric oxide dioxygenase (NOD) activity that allows it to relieve nitrosative stress and enhance in vivo survival of its host. Despite its small size, the protein matrix of HbN hosts a two-branched tunnel, consisting of orthogonal short and long channels, that connects the heme active site to the protein surface. A novel dual-path mechanism has been suggested to drive migration of O(2) and NO to the distal heme cavity. While oxygen migrates mainly by the short path, a ligand-induced conformational change regulates opening of the long tunnel branch for NO, via a phenylalanine (PheE15) residue that acts as a gate. Site-directed mutagenesis and molecular simulations have been used to examine the gating role played by PheE15 in modulating the NOD function of HbN. Mutants carrying replacement of PheE15 with alanine, isoleucine, tyrosine and tryptophan have similar O(2)/CO association kinetics, but display significant reduction in their NOD function. Molecular simulations substantiated that mutation at the PheE15 gate confers significant changes in the long tunnel, and therefore may affect the migration of ligands. These results support the pivotal role of PheE15 gate in modulating the diffusion of NO via the long tunnel branch in the oxygenated protein, and hence the NOD function of HbN.Ana OliveiraSandeep SinghAxel Bidon-ChanalFlavio FortiMarcelo A MartíLeonardo BoechiDario A EstrinKanak L DikshitF Javier LuquePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e49291 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ana Oliveira Sandeep Singh Axel Bidon-Chanal Flavio Forti Marcelo A Martí Leonardo Boechi Dario A Estrin Kanak L Dikshit F Javier Luque Role of PheE15 gate in ligand entry and nitric oxide detoxification function of mycobacterium tuberculosis truncated hemoglobin N.
description	The truncated hemoglobin N, HbN, of Mycobacterium tuberculosis is endowed with a potent nitric oxide dioxygenase (NOD) activity that allows it to relieve nitrosative stress and enhance in vivo survival of its host. Despite its small size, the protein matrix of HbN hosts a two-branched tunnel, consisting of orthogonal short and long channels, that connects the heme active site to the protein surface. A novel dual-path mechanism has been suggested to drive migration of O(2) and NO to the distal heme cavity. While oxygen migrates mainly by the short path, a ligand-induced conformational change regulates opening of the long tunnel branch for NO, via a phenylalanine (PheE15) residue that acts as a gate. Site-directed mutagenesis and molecular simulations have been used to examine the gating role played by PheE15 in modulating the NOD function of HbN. Mutants carrying replacement of PheE15 with alanine, isoleucine, tyrosine and tryptophan have similar O(2)/CO association kinetics, but display significant reduction in their NOD function. Molecular simulations substantiated that mutation at the PheE15 gate confers significant changes in the long tunnel, and therefore may affect the migration of ligands. These results support the pivotal role of PheE15 gate in modulating the diffusion of NO via the long tunnel branch in the oxygenated protein, and hence the NOD function of HbN.
format	article
author	Ana Oliveira Sandeep Singh Axel Bidon-Chanal Flavio Forti Marcelo A Martí Leonardo Boechi Dario A Estrin Kanak L Dikshit F Javier Luque
author_facet	Ana Oliveira Sandeep Singh Axel Bidon-Chanal Flavio Forti Marcelo A Martí Leonardo Boechi Dario A Estrin Kanak L Dikshit F Javier Luque
author_sort	Ana Oliveira
title	Role of PheE15 gate in ligand entry and nitric oxide detoxification function of mycobacterium tuberculosis truncated hemoglobin N.
title_short	Role of PheE15 gate in ligand entry and nitric oxide detoxification function of mycobacterium tuberculosis truncated hemoglobin N.
title_full	Role of PheE15 gate in ligand entry and nitric oxide detoxification function of mycobacterium tuberculosis truncated hemoglobin N.
title_fullStr	Role of PheE15 gate in ligand entry and nitric oxide detoxification function of mycobacterium tuberculosis truncated hemoglobin N.
title_full_unstemmed	Role of PheE15 gate in ligand entry and nitric oxide detoxification function of mycobacterium tuberculosis truncated hemoglobin N.
title_sort	role of phee15 gate in ligand entry and nitric oxide detoxification function of mycobacterium tuberculosis truncated hemoglobin n.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/d4fa0b2d6d6c4787a9cfc4e8faf134e9
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Role of PheE15 gate in ligand entry and nitric oxide detoxification function of mycobacterium tuberculosis truncated hemoglobin N.

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