Dynamical Regulation of Ligand Migration by a Gate-Opening Molecular Switch in Truncated Hemoglobin-N from Mycobacterium tuberculosis

A. BIDON-CHANAL; M. A. MARTI; D.A. ESTRIN; F.J. LUQUE

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

American Chemical Society

Lugar: Columbus, OH; Año: 2007 vol. 129 p. 6782 - 6788

0002-7863

           Truncated hemoglobin-N is believed to constitute a defense mechanism of Mycobacteriumtuberculosis against NO produced by macrophages, which is converted to the harmless nitrate anion. Thisprocess is catalyzed very efficiently, as the enzyme activity is limited by ligand diffusion. By using extendedmolecular 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 thehypothesis 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 theheme group triggers local conformational changes in the TyrB10-GlnE11 pair, which favor opening of thePheE15 gate residue through global changes in the essential motions of the protein skeleton. The complexpattern of conformational changes triggered upon O2 binding is drastically altered in the GlnE11fAla andTyrB10fPhe mutants, which justifies the poor enzymatic activity observed experimentally for theTyrB10fPhe form. The results support a molecular mechanism evolved to ensure access of NO to theheme cavity in the oxygenated form of the protein, which should warrant survival of the microorganismunder stress conditions.