Dynamical characterization of the Heme NO Oxygen binding (HNOX) domain. Insight into soluble guanylate cyclase allosteric transition.

LUCIANA CAPECE; DARIO A. ESTRIN; MARCELO A. MARTI

BIOCHEMISTRY

AMER CHEMICAL SOC

Año: 2008 vol. 47 p. 9416 - 9427

0006-2960

Since the discovery of soluble guanylate cyclase (sGC) as the mammalian receptor for nitric oxide (NO) numerous studies have been performed in order to understand how sGC transduces the NO signal. However, the structural basis of sGC activation is still not completely elucidated. Spectroscopic and kinetic studies showed that the key step in the activation mechanism was the NO induced breaking of the iron proximal histidine bond in the so called 6c-NO to 5c-NO transition. The main breakthrough in the understanding of sGC activation mechanism came however from the elucidation of crystal structures for two different prokaryotic Heme NO Oxygen (HNOX) domains, which are homologues to the sGC heme domain. In this work we present computer simulation results of Thermoanaerobacter tencogensis HNOX, that complement these structural studies yielding molecular explanations to several poorly understood properties of these proteins. Specifically, our results explain the differential ligand binding patterns of the HNOX domains according to the nature of proximal and distal residues. We also show that the natural dynamics of these proteins is intimately related with the proposed conformational dependent activation process, which involves mainly the áFâ1 loop and the áA-áC distal subdomain. The results from the sGC models also support this view and suggest a key role for the áFâ1 loop in the iron proximal histidine bond breaking process and therefore, in the sGC activation mechanism.