Abstract:
Mycobacterium tuberculosis, the causative agent of human tuberculosis, is forced into latency by nitric oxide produced by macrophages during infection. In response to nitrosative stress M. tuberculosis has evolved a defense mechanism that relies on the oxygenated form of "truncated hemoglobin" N (trHbN), formally acting as NO-dioxygenase, yielding the harmless nitrate ion. X-ray crystal structures have shown that trHbN hosts a two-branched protein matrix tunnel system, proposed to control diatomic ligand migration to the heme, as the rate-limiting step in NO conversion to nitrate. Extended molecular dynamics simulations (0.1 μs), employed here to characterize the factors controlling diatomic ligand diffusion through the apolar tunnel system, suggest that O2 migration in deoxy-trHbN is restricted to a short branch of the tunnel, and that O2 binding to the heme drives conformational and dynamical fluctuations promoting NO migration through the long tunnel branch. The simulation results suggest that trHbN has evolved a dual-path mechanism for migration of O2 and NO to the heme, to achieve the most efficient NO detoxification. © 2006 Wiley-Liss, Inc.
Registro:
Documento: |
Artículo
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Título: | Ligand-induced dynamical regulation of NO conversion in Mycobacterium tuberculosis truncated hemoglobin-N |
Autor: | Bidon-Chanal, A.; Martí, M.A.; Crespo, A.; Milani, M.; Orozco, M.; Bolognesi, M.; Luque, F.J.; Estrin, D.A. |
Filiación: | Departament de Fisicoquímica, Facultat de Farmacia, Universität de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain Departamento de Quimica Inorganica, Analitica y Quimica Fisica/INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428EHA, Argentina Department of Biomolecular Sciences and Biotechnology, CNR-INFM, University of Milano, Milano, Italy Departament de Bioquímica i Biologia Molecular, Facultat de Química, Universitat de Barcelona, Martí i Franqués 1, 08028 Barcelona, Spain Unidad de Modelización Molecular y Bioinformática, Parc Científic de Barcelona, Josep Samitier 1-6, 08028 Barcelona, Spain Span and Computacional Biology Program, Barcelona Supercomputing Center, Edificio Nexus II, Barcelona 08028, Spain University of Buenos Aires, Department of Chemistry, Ciudad Universitaria, Buenos Aires, C1428EHA, Argentina University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain
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Palabras clave: | Ligand migration; M. tuberculosis; Molecular dynamics; Nitric oxide; deoxy truncated hemoglobin n; dioxygenase; heme; hemoglobin; ligand; nitrate; nitric oxide; oxygen; truncated hemoglobin n; unclassified drug; article; bioinformatics; conformational transition; crystal structure; defense mechanism; diffusion; latent period; macrophage; molecular dynamics; Mycobacterium tuberculosis; nitrosation; nonhuman; oxygen affinity; priority journal; protein conformation; protein function; simulation; structure analysis; X ray crystallography; Mycobacterium tuberculosis |
Año: | 2006
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Volumen: | 64
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Número: | 2
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Página de inicio: | 457
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Página de fin: | 464
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DOI: |
http://dx.doi.org/10.1002/prot.21004 |
Título revista: | Proteins: Structure, Function and Genetics
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Título revista abreviado: | Proteins Struct. Funct. Genet.
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ISSN: | 08873585
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CODEN: | PSFGE
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CAS: | dioxygenase, 37292-90-3; heme, 14875-96-8; hemoglobin, 9008-02-0; nitrate, 14797-55-8; nitric oxide, 10102-43-9; oxygen, 7782-44-7
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Registro: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08873585_v64_n2_p457_BidonChanal |
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Citas:
---------- APA ----------
Bidon-Chanal, A., Martí, M.A., Crespo, A., Milani, M., Orozco, M., Bolognesi, M., Luque, F.J.,..., Estrin, D.A.
(2006)
. Ligand-induced dynamical regulation of NO conversion in Mycobacterium tuberculosis truncated hemoglobin-N. Proteins: Structure, Function and Genetics, 64(2), 457-464.
http://dx.doi.org/10.1002/prot.21004---------- CHICAGO ----------
Bidon-Chanal, A., Martí, M.A., Crespo, A., Milani, M., Orozco, M., Bolognesi, M., et al.
"Ligand-induced dynamical regulation of NO conversion in Mycobacterium tuberculosis truncated hemoglobin-N"
. Proteins: Structure, Function and Genetics 64, no. 2
(2006) : 457-464.
http://dx.doi.org/10.1002/prot.21004---------- MLA ----------
Bidon-Chanal, A., Martí, M.A., Crespo, A., Milani, M., Orozco, M., Bolognesi, M., et al.
"Ligand-induced dynamical regulation of NO conversion in Mycobacterium tuberculosis truncated hemoglobin-N"
. Proteins: Structure, Function and Genetics, vol. 64, no. 2, 2006, pp. 457-464.
http://dx.doi.org/10.1002/prot.21004---------- VANCOUVER ----------
Bidon-Chanal, A., Martí, M.A., Crespo, A., Milani, M., Orozco, M., Bolognesi, M., et al. Ligand-induced dynamical regulation of NO conversion in Mycobacterium tuberculosis truncated hemoglobin-N. Proteins Struct. Funct. Genet. 2006;64(2):457-464.
http://dx.doi.org/10.1002/prot.21004