Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis
Truncated hemoglobin-N is believed to constitute a defense mechanism of Mycobacterium tuberculosis against NO produced by macrophages, which is converted to the harmless nitrate anion. This process is catalyzed very efficiently, as the enzyme activity is limited by ligand diffusion. By using extende...
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2007
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v129_n21_p6782_BidonChanal http://hdl.handle.net/20.500.12110/paper_00027863_v129_n21_p6782_BidonChanal |
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paper:paper_00027863_v129_n21_p6782_BidonChanal2023-06-08T14:22:42Z Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis Martí, Marcelo Adrián Estrin, Dario Ariel Dynamical regulation Ligand migration Molecular mechanisms Mycobacterium tuberculosis Conformations Enzyme activity Hemoglobin Macrophages Molecular dynamics Negative ions Nitrogen oxides Ligands glycine hemoglobin hemoglobin n ligand phenylalanine tyrosine unclassified drug article conformational transition diffusion enzyme activity molecular dynamics Mycobacterium tuberculosis nonhuman oxygen affinity regulatory mechanism simulation Amino Acid Substitution Computer Simulation Hemoglobins Hydrogen Bonding Ligands Models, Molecular Mycobacterium tuberculosis Oxygen Oxygenases Protein Conformation Truncated hemoglobin-N is believed to constitute a defense mechanism of Mycobacterium tuberculosis against NO produced by macrophages, which is converted to the harmless nitrate anion. This process is catalyzed very efficiently, as the enzyme activity is limited by ligand diffusion. By using extended molecular dynamics simulations we explore the mechanism that regulates ligand diffusion and, particularly, the role played by residues that assist binding of O2 to the heme group. Our data strongly support the hypothesis that the access of NO to the heme cavity is dynamically regulated by the TyrB10-GlnE11 pair, which acts as a molecular switch that controls opening of the ligand diffusion tunnel. Binding of O2 to the heme group triggers local conformational changes in the TyrB10-GlnE11 pair, which favor opening of the PheE15 gate residue through global changes in the essential motions of the protein skeleton. The complex pattern of conformational changes triggered upon O2 binding is drastically altered in the GlnE11→Ala and TyrB10→Phe mutants, which justifies the poor enzymatic activity observed experimentally for the TyrB10→Phe form. The results support a molecular mechanism evolved to ensure access of NO to the heme cavity in the oxygenated form of the protein, which should warrant survival of the microorganism under stress conditions. © 2007 American Chemical Society. Fil:Martí, M.A. 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. 2007 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v129_n21_p6782_BidonChanal http://hdl.handle.net/20.500.12110/paper_00027863_v129_n21_p6782_BidonChanal |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Dynamical regulation Ligand migration Molecular mechanisms Mycobacterium tuberculosis Conformations Enzyme activity Hemoglobin Macrophages Molecular dynamics Negative ions Nitrogen oxides Ligands glycine hemoglobin hemoglobin n ligand phenylalanine tyrosine unclassified drug article conformational transition diffusion enzyme activity molecular dynamics Mycobacterium tuberculosis nonhuman oxygen affinity regulatory mechanism simulation Amino Acid Substitution Computer Simulation Hemoglobins Hydrogen Bonding Ligands Models, Molecular Mycobacterium tuberculosis Oxygen Oxygenases Protein Conformation |
| spellingShingle |
Dynamical regulation Ligand migration Molecular mechanisms Mycobacterium tuberculosis Conformations Enzyme activity Hemoglobin Macrophages Molecular dynamics Negative ions Nitrogen oxides Ligands glycine hemoglobin hemoglobin n ligand phenylalanine tyrosine unclassified drug article conformational transition diffusion enzyme activity molecular dynamics Mycobacterium tuberculosis nonhuman oxygen affinity regulatory mechanism simulation Amino Acid Substitution Computer Simulation Hemoglobins Hydrogen Bonding Ligands Models, Molecular Mycobacterium tuberculosis Oxygen Oxygenases Protein Conformation Martí, Marcelo Adrián Estrin, Dario Ariel Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis |
| topic_facet |
Dynamical regulation Ligand migration Molecular mechanisms Mycobacterium tuberculosis Conformations Enzyme activity Hemoglobin Macrophages Molecular dynamics Negative ions Nitrogen oxides Ligands glycine hemoglobin hemoglobin n ligand phenylalanine tyrosine unclassified drug article conformational transition diffusion enzyme activity molecular dynamics Mycobacterium tuberculosis nonhuman oxygen affinity regulatory mechanism simulation Amino Acid Substitution Computer Simulation Hemoglobins Hydrogen Bonding Ligands Models, Molecular Mycobacterium tuberculosis Oxygen Oxygenases Protein Conformation |
| description |
Truncated hemoglobin-N is believed to constitute a defense mechanism of Mycobacterium tuberculosis against NO produced by macrophages, which is converted to the harmless nitrate anion. This process is catalyzed very efficiently, as the enzyme activity is limited by ligand diffusion. By using extended molecular dynamics simulations we explore the mechanism that regulates ligand diffusion and, particularly, the role played by residues that assist binding of O2 to the heme group. Our data strongly support the hypothesis that the access of NO to the heme cavity is dynamically regulated by the TyrB10-GlnE11 pair, which acts as a molecular switch that controls opening of the ligand diffusion tunnel. Binding of O2 to the heme group triggers local conformational changes in the TyrB10-GlnE11 pair, which favor opening of the PheE15 gate residue through global changes in the essential motions of the protein skeleton. The complex pattern of conformational changes triggered upon O2 binding is drastically altered in the GlnE11→Ala and TyrB10→Phe mutants, which justifies the poor enzymatic activity observed experimentally for the TyrB10→Phe form. The results support a molecular mechanism evolved to ensure access of NO to the heme cavity in the oxygenated form of the protein, which should warrant survival of the microorganism under stress conditions. © 2007 American Chemical Society. |
| author |
Martí, Marcelo Adrián Estrin, Dario Ariel |
| author_facet |
Martí, Marcelo Adrián Estrin, Dario Ariel |
| author_sort |
Martí, Marcelo Adrián |
| title |
Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis |
| title_short |
Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis |
| title_full |
Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis |
| title_fullStr |
Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis |
| title_full_unstemmed |
Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis |
| title_sort |
dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-n from mycobacterium tuberculosis |
| publishDate |
2007 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v129_n21_p6782_BidonChanal http://hdl.handle.net/20.500.12110/paper_00027863_v129_n21_p6782_BidonChanal |
| work_keys_str_mv |
AT martimarceloadrian dynamicalregulationofligandmigrationbyagateopeningmolecularswitchintruncatedhemoglobinnfrommycobacteriumtuberculosis AT estrindarioariel dynamicalregulationofligandmigrationbyagateopeningmolecularswitchintruncatedhemoglobinnfrommycobacteriumtuberculosis |
| _version_ |
1768543062518136832 |