Ligand-induced dynamical regulation of NO conversion in Mycobacterium tuberculosis truncated-hemoglobin-N

A. BIDON CHANAL; M. MARTI; A. CRESPO; M. MILANI; M. OROZCO; M. BOLOGNESI; F.J. LUQUE; D.A. ESTRIN

PROTEINS: STRUCTURE, FUNCTION AND GENETICS

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2006 vol. 67 p. 457 - 464

0887-3585

ABSTRACT Mycobacterium tuberculosis, thecausative agent of human tuberculosis, is forcedinto latency by nitric oxide produced by macrophagesduring infection. In response to nitrosativestress M. tuberculosis has evolved a defense mechanismthat relies on the oxygenated form of ?truncatedhemoglobin? N (trHbN), formally acting asNO-dioxygenase, yielding the harmless nitrate ion.X-ray crystal structures have shown that trHbNhosts a two-branched protein matrix tunnel system,proposed to control diatomic ligand migration tothe heme, as the rate-limiting step in NO conversionto nitrate. Extended molecular dynamics simulations(0.1 s), employed here to characterize thefactors controlling diatomic ligand diffusion throughthe apolar tunnel system, suggest that O2 migrationin deoxy-trHbN is restricted to a short branch of thetunnel, and that O2 binding to the heme drivesconformational and dynamical fluctuations promotingNO migration through the long tunnel branch.The simulation results suggest that trHbN hasevolved a dual-path mechanism for migration of O2and NO to the heme, to achieve the most efficient NOdetoxification.