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, O-2; 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 O-2 wheras others, such as sGC, show no measurable affinity for O-2. A molecular basis for this ligand selectivity has now been established. A distal pocket tyrosine is requisite for O-2 binding and is used to kinetically distinguish between NO and O-2, In the absence of this tyrosine, the O-2 dissociation rate is so fast that the O-2 complex is never formed, whereas the rate of NO dissociation remains essentially unchanged, thus providing discrimination.