Ligand discrimination in soluble guanylate cyclase and the H-NOX family of heme sensor proteins

Soluble guanylate cyclases (sGCs) are eukaryotic heme sensor proteins that selectively bind NO in the presence of a large excess of the similar diatomic gas, O₂; this discrimination is essential for NO signaling. Recent discoveries place sGC in the H-NOX (heme nitric oxide and/or oxygen binding domain) family that includes bacterial proteins. The defining characteristic of this family is that some H-NOX proteins tightly bind O₂ wheras others, such as sGC, show no measurable affinity for O₂. A molecular basis for this ligand selectivity has now been established. A distal pocket tyrosine is requisite for O₂ binding and is used to kinetically distinguish between NO and O₂. In the absence of this tyrosine, the O₂ dissociation rate is so fast that the O₂ complex is never formed, whereas the rate of NO dissociation remains essentially unchanged, thus providing discrimination.