title: Structure and Activation of Soluble Guanylyl Cyclase, the Nitric Oxide Sensor.
abstract: Soluble guanylyl/guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) and is central to the physiology of blood pressure regulation, wound healing, memory formation, and other key physiological activities. sGC is increasingly implicated in disease and is targeted by novel therapeutic compounds. The protein displays a rich evolutionary history and a fascinating signal transduction mechanism, with NO binding to an N-terminal heme-containing domain, which activates the C-terminal cyclase domains. Recent Advances: Crystal structures of individual sGC domains or their bacterial homologues coupled with small-angle x-ray scattering, electron microscopy, chemical cross-linking, and Förster resonance energy transfer measurements are yielding insight into the overall structure for sGC, which is elongated and likely quite dynamic. Transient kinetic measurements reveal a role for individual domains in lowering NO affinity for heme. New sGC stimulatory drugs are now in the clinic and appear to function through binding near or directly to the sGC heme domain, relieving inhibitory contacts with other domains. New sGC-activating drugs show promise for recovering oxidized sGC in diseases with high inflammation by replacing lost heme.
  
  
  
  Despite the many recent advances, sGC regulation, NO activation, and mechanisms of drug binding remain unclear. Here, we describe the molecular evolution of sGC, new molecular models, and the linked equilibria between sGC NO binding, drug binding, and catalytic activity.
  
  
  
  Recent results and ongoing studies lay the foundation for a complete understanding of structure and mechanism, and they open the door for new drug discovery targeting sGC. Antioxid. Redox Signal. 26, 107-121.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona.
authors.forename: William R
authors.initials: WR
authors.lastname: Montfort
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Wales
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Weichsel
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004789:Enzyme Activation; D015870:Gene Expression; D006160:Guanosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D006162:Guanylate Cyclase / Q000737:chemistry / Q000378:metabolism; D006418:Heme / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009569:Nitric Oxide / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021122:Protein Subunits; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D021122:Protein Subunits; D009569:Nitric Oxide; D006418:Heme; D006160:Guanosine Triphosphate; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
keywords: H-NOX domain; coiled-coil domain; guanylate cyclase; hypertension; molecular evolution; stimulator compound