Role of PheE15 Gate in Ligand Entry and Nitric Oxide Detoxification Function of Mycobacterium tuberculosis Truncated Hemoglobin N
- Autores
- Oliveira, A.; Singh, S.; Bidon-Chanal, A.; Forti, F.; Martí, M.A.; Boechi, L.; Estrin, D.A.; Dikshit, K.L.; Luque, F.J.
- Año de publicación
- 2012
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- 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. © 2012 Oliveira et al.
 Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
 Fil:Boechi, L. 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.
- Fuente
- PLoS ONE 2012;7(11)
- Materia
- 
            
        alanine
 dioxygenase
 heme
 isoleucine
 nitric oxide dioxygenase
 oxygen
 phenylalanine
 phenylalanine 15
 truncated hemoglobin
 truncated hemoglobin N
 tryptophan
 tyrosine
 unclassified drug
 article
 conformational transition
 controlled study
 detoxification
 down regulation
 enzyme activity
 ligand binding
 molecular dynamics
 mutant
 mutational analysis
 Mycobacterium tuberculosis
 nonhuman
 oxidation
 oxygen affinity
 site directed mutagenesis
 structure analysis
 wild type
 Bacterial Proteins
 Binding Sites
 Carbon Monoxide
 Computer Simulation
 Crystallography, X-Ray
 Ligands
 Mutagenesis, Site-Directed
 Mycobacterium tuberculosis
 Nitric Oxide
 Oxygen
 Phenylalanine
 Protein Structure, Tertiary
 Truncated Hemoglobins
 Mycobacterium tuberculosis
- Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- http://creativecommons.org/licenses/by/2.5/ar
- Repositorio
.jpg) 
- Institución
- Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
- OAI Identificador
- paperaa:paper_19326203_v7_n11_p_Oliveira
Ver los metadatos del registro completo
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|---|---|
| oai_identifier_str | paperaa:paper_19326203_v7_n11_p_Oliveira | 
| network_acronym_str | BDUBAFCEN | 
| repository_id_str | 1896 | 
| network_name_str | Biblioteca Digital (UBA-FCEN) | 
| spelling | Role of PheE15 Gate in Ligand Entry and Nitric Oxide Detoxification Function of Mycobacterium tuberculosis Truncated Hemoglobin NOliveira, A.Singh, S.Bidon-Chanal, A.Forti, F.Martí, M.A.Boechi, L.Estrin, D.A.Dikshit, K.L.Luque, F.J.alaninedioxygenasehemeisoleucinenitric oxide dioxygenaseoxygenphenylalaninephenylalanine 15truncated hemoglobintruncated hemoglobin Ntryptophantyrosineunclassified drugarticleconformational transitioncontrolled studydetoxificationdown regulationenzyme activityligand bindingmolecular dynamicsmutantmutational analysisMycobacterium tuberculosisnonhumanoxidationoxygen affinitysite directed mutagenesisstructure analysiswild typeBacterial ProteinsBinding SitesCarbon MonoxideComputer SimulationCrystallography, X-RayLigandsMutagenesis, Site-DirectedMycobacterium tuberculosisNitric OxideOxygenPhenylalanineProtein Structure, TertiaryTruncated HemoglobinsMycobacterium tuberculosisThe 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. © 2012 Oliveira et al.Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Boechi, L. 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.2012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://hdl.handle.net/20.500.12110/paper_19326203_v7_n11_p_OliveiraPLoS ONE 2012;7(11)reponame:Biblioteca Digital (UBA-FCEN)instname:Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturalesinstacron:UBA-FCENenginfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/2.5/ar2025-10-30T11:21:04Zpaperaa:paper_19326203_v7_n11_p_OliveiraInstitucionalhttps://digital.bl.fcen.uba.ar/Universidad públicaNo correspondehttps://digital.bl.fcen.uba.ar/cgi-bin/oaiserver.cgiana@bl.fcen.uba.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:18962025-10-30 11:21:05.396Biblioteca Digital (UBA-FCEN) - Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturalesfalse | 
| dc.title.none.fl_str_mv | Role of PheE15 Gate in Ligand Entry and Nitric Oxide Detoxification Function of Mycobacterium tuberculosis Truncated Hemoglobin N | 
| title | Role of PheE15 Gate in Ligand Entry and Nitric Oxide Detoxification Function of Mycobacterium tuberculosis Truncated Hemoglobin N | 
| spellingShingle | Role of PheE15 Gate in Ligand Entry and Nitric Oxide Detoxification Function of Mycobacterium tuberculosis Truncated Hemoglobin N Oliveira, A. alanine dioxygenase heme isoleucine nitric oxide dioxygenase oxygen phenylalanine phenylalanine 15 truncated hemoglobin truncated hemoglobin N tryptophan tyrosine unclassified drug article conformational transition controlled study detoxification down regulation enzyme activity ligand binding molecular dynamics mutant mutational analysis Mycobacterium tuberculosis nonhuman oxidation oxygen affinity site directed mutagenesis structure analysis wild type Bacterial Proteins Binding Sites Carbon Monoxide Computer Simulation Crystallography, X-Ray Ligands Mutagenesis, Site-Directed Mycobacterium tuberculosis Nitric Oxide Oxygen Phenylalanine Protein Structure, Tertiary Truncated Hemoglobins Mycobacterium tuberculosis | 
| 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 | 
| dc.creator.none.fl_str_mv | Oliveira, A. Singh, S. Bidon-Chanal, A. Forti, F. Martí, M.A. Boechi, L. Estrin, D.A. Dikshit, K.L. Luque, F.J. | 
| author | Oliveira, A. | 
| author_facet | Oliveira, A. Singh, S. Bidon-Chanal, A. Forti, F. Martí, M.A. Boechi, L. Estrin, D.A. Dikshit, K.L. Luque, F.J. | 
| author_role | author | 
| author2 | Singh, S. Bidon-Chanal, A. Forti, F. Martí, M.A. Boechi, L. Estrin, D.A. Dikshit, K.L. Luque, F.J. | 
| author2_role | author author author author author author author author | 
| dc.subject.none.fl_str_mv | alanine dioxygenase heme isoleucine nitric oxide dioxygenase oxygen phenylalanine phenylalanine 15 truncated hemoglobin truncated hemoglobin N tryptophan tyrosine unclassified drug article conformational transition controlled study detoxification down regulation enzyme activity ligand binding molecular dynamics mutant mutational analysis Mycobacterium tuberculosis nonhuman oxidation oxygen affinity site directed mutagenesis structure analysis wild type Bacterial Proteins Binding Sites Carbon Monoxide Computer Simulation Crystallography, X-Ray Ligands Mutagenesis, Site-Directed Mycobacterium tuberculosis Nitric Oxide Oxygen Phenylalanine Protein Structure, Tertiary Truncated Hemoglobins Mycobacterium tuberculosis | 
| topic | alanine dioxygenase heme isoleucine nitric oxide dioxygenase oxygen phenylalanine phenylalanine 15 truncated hemoglobin truncated hemoglobin N tryptophan tyrosine unclassified drug article conformational transition controlled study detoxification down regulation enzyme activity ligand binding molecular dynamics mutant mutational analysis Mycobacterium tuberculosis nonhuman oxidation oxygen affinity site directed mutagenesis structure analysis wild type Bacterial Proteins Binding Sites Carbon Monoxide Computer Simulation Crystallography, X-Ray Ligands Mutagenesis, Site-Directed Mycobacterium tuberculosis Nitric Oxide Oxygen Phenylalanine Protein Structure, Tertiary Truncated Hemoglobins Mycobacterium tuberculosis | 
| dc.description.none.fl_txt_mv | 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. © 2012 Oliveira et al. Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Boechi, L. 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. | 
| 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. © 2012 Oliveira et al. | 
| publishDate | 2012 | 
| dc.date.none.fl_str_mv | 2012 | 
| 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/20.500.12110/paper_19326203_v7_n11_p_Oliveira | 
| url | http://hdl.handle.net/20.500.12110/paper_19326203_v7_n11_p_Oliveira | 
| dc.language.none.fl_str_mv | eng | 
| language | eng | 
| dc.rights.none.fl_str_mv | info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar | 
| eu_rights_str_mv | openAccess | 
| rights_invalid_str_mv | http://creativecommons.org/licenses/by/2.5/ar | 
| dc.format.none.fl_str_mv | application/pdf | 
| dc.source.none.fl_str_mv | PLoS ONE 2012;7(11) reponame:Biblioteca Digital (UBA-FCEN) instname:Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales instacron:UBA-FCEN | 
| reponame_str | Biblioteca Digital (UBA-FCEN) | 
| collection | Biblioteca Digital (UBA-FCEN) | 
| instname_str | Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales | 
| instacron_str | UBA-FCEN | 
| institution | UBA-FCEN | 
| repository.name.fl_str_mv | Biblioteca Digital (UBA-FCEN) - Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales | 
| repository.mail.fl_str_mv | ana@bl.fcen.uba.ar | 
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| score | 13.10058 |