Hypertension (high blood pressure) affects approximately one third of US adults and increases the risk for heart disease and stroke. The mammalian nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), acts within vascular signaling pathways that lower blood pressure. Treatment for certain forms of hypertension include the stimulation of sGC with small-molecule drugs, however the binding pocket and the mechanism of action of these drugs have thus far been elusive. Here, we present the full-length structure of the holoenzyme sGC in both inactive and active states as solved by cryo-electron microscopy. sGC adopts a contracted position in its inactive state that rotates and extends to activate upon addition of NO. In solution small angle X-ray scattering measurements corroborate the extension observed by cryo-electron microscopy. A drug-like molecule binds directly between the gas-sensing region and the hinge region of the protein in a pocket only formed in the active state, suggesting a stabilizing interaction. The location of the drug binding pocket and hypotheses for its mechanism of action usher in a new era in the study of sGC for both academic and pharmaceutical research, with the potential to transform the way sGC is targeted in hypertension.

Allosteric activation of the mammalian nitric oxide receptor induces a distinct conformational rearrangement

ACS Fall 2020 Virtual Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.