A new paradigm for gaseous ligand selectivity of hemoproteins highlighted by soluble guanylate cyclase.

Nitric oxide (NO), carbon monoxide (CO), and oxygen (O) are important physiological messengers whose concentrations vary in a remarkable range, [NO] typically from nM to several μM while [O] reaching to hundreds of μM. One of the machineries evolved in living organisms for gas sensing is sensor hemoproteins whose conformational change upon gas binding triggers downstream response cascades. The recently proposed "sliding scale rule" hypothesis provides a general interpretation for gaseous ligand selectivity of hemoproteins, identifying five factors that govern gaseous ligand selectivity. Hemoproteins have intrinsic selectivity for the three gases due to a neutral proximal histidine ligand while proximal strain of heme and distal steric hindrance indiscriminately adjust the affinity of these three gases for heme. On the other hand, multiple-step NO binding and distal hydrogen bond donor(s) specifically enhance affinity for NO and O, respectively. The "sliding scale rule" hypothesis provides clear interpretation for dramatic selectivity for NO over O in soluble guanylate cyclase (sGC) which is an important example of sensor hemoproteins and plays vital roles in a wide range of physiological functions. The "sliding scale rule" hypothesis has so far been validated by all experimental data and it may guide future designs for heme-based gas sensors.