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.