Mechanistic insights into nitric oxide activation of H‐NOX sensor proteins (1013.18)

Abstract

Nitric oxide (NO) is a freely diffusible gas that is critical for normal cardiovascular function through the regulation of processes such as blood vessel homeostasis and inhibition of platelet aggregation. An integral component of mammalian NO signaling is soluble guanylate cyclase (sGC), the primary receptor for NO, whereby sensitive and selective binding of NO to its heme‐containing H‐NOX domain results in conversion of guanosine triphosphate (GTP) to the secondary messenger cyclic guanosine monophosphate (cGMP). The heme cofactor of sGC exists in a 5‐coordinate ferrous state (Fe(II)) with histidine as the proximal ligand. NO binding to the distal heme site yields a transient 6‐coordinate complex where, the trans effect exhibited by NO weakens the iron‐histidine bond resulting in histidine dissociation to yield an active, 5‐coordinate NO complex (Fe(II)‐NO). Several biochemical studies have determined that severing of the iron‐histidine bond is required for activation, however, the lack of a 5‐coordinate NO H‐NOX structure has limited molecular level insights into the NO activation mechanism. Toward this end, crystal structures of a bacterial H‐NOX protein free and complexed with NO have been determined and reveal a conformational change resulting from the breakage of the iron‐histidine bond. It is hypothesized that this conformational change is the mechanism by which H‐NOX proteins regulate their signaling effector partners.