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Abstract:

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.

Registro:

Documento: Artículo
Título:Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis
Autor:Bidon-Chanal, A.; Martí, M.A.; Estrin, D.A.; Luque, F.J.
Filiación:Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona, Avenida Diagonal 643, 08028, Barcelona, Spain
Departamento de Quimica Inorganica, Analitica Y Quimica Fisica/INQUIMAE-CONICET, Facultad de Ciencias Exactas Y Naturales, Pabellón 2, Buenos Aires, CI428EHA, Argentina
Palabras clave: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
Año:2007
Volumen:129
Número:21
Página de inicio:6782
Página de fin:6788
DOI: http://dx.doi.org/10.1021/ja0689987
Título revista:Journal of the American Chemical Society
Título revista abreviado:J. Am. Chem. Soc.
ISSN:00027863
CODEN:JACSA
CAS:glycine, 56-40-6, 6000-43-7, 6000-44-8; hemoglobin, 9008-02-0; phenylalanine, 3617-44-5, 63-91-2; tyrosine, 16870-43-2, 55520-40-6, 60-18-4; Hemoglobins; Ligands; Oxygen, 7782-44-7; Oxygenases, 1.13.-; nitric oxide dioxygenase, 1.14.13.-
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v129_n21_p6782_BidonChanal

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Citas:

---------- APA ----------
Bidon-Chanal, A., Martí, M.A., Estrin, D.A. & Luque, F.J. (2007) . Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis. Journal of the American Chemical Society, 129(21), 6782-6788.
http://dx.doi.org/10.1021/ja0689987
---------- CHICAGO ----------
Bidon-Chanal, A., Martí, M.A., Estrin, D.A., Luque, F.J. "Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis" . Journal of the American Chemical Society 129, no. 21 (2007) : 6782-6788.
http://dx.doi.org/10.1021/ja0689987
---------- MLA ----------
Bidon-Chanal, A., Martí, M.A., Estrin, D.A., Luque, F.J. "Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis" . Journal of the American Chemical Society, vol. 129, no. 21, 2007, pp. 6782-6788.
http://dx.doi.org/10.1021/ja0689987
---------- VANCOUVER ----------
Bidon-Chanal, A., Martí, M.A., Estrin, D.A., Luque, F.J. Dynamical regulation of ligand migration by a gate-opening molecular switch in truncated hemoglobin-N from Mycobacterium tuberculosis. J. Am. Chem. Soc. 2007;129(21):6782-6788.
http://dx.doi.org/10.1021/ja0689987