A molecular basis for NO selectivity in soluble guanylate cyclase.
Soluble guanylate cyclases (sGCs) function as heme sensors that selectively bind nitric oxide (NO), triggering reactions essential to animal physiology. Recent discoveries place sGCs in the H-NOX family (heme nitric oxide/oxygen-binding domain), which includes bacterial proteins from aerobic and anaerobic organisms. Some H-NOX proteins tightly bind oxygen (O2), whereas others show no measurable affinity for O2, providing the basis for selective NO signaling in aerobic cells. Using a series of wild-type and mutant H-NOXs, we established a molecular basis for ligand discrimination. A distal pocket tyrosine is requisite for O2 binding in the H-NOX family. These data suggest that sGC uses a kinetic selection against O2; we propose that the O2 dissociation rate in the absence of this tyrosine is fast and that a stable O2 complex does not form.
Boon
Elizabeth M
EM
Department of Chemistry, University of California, Berkeley, California 94720, USA.
Huang
Shirley H
SH
Marletta
Michael A
MA
D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001667:Binding, Competitive; D015374:Biosensing Techniques; D006162:Guanylate Cyclase; D006420:Hemeproteins / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry*; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D000071756:Soluble Guanylyl Cyclase; D046950:Thermoanaerobacterium / Q000737:chemistry
D001426:Bacterial Proteins; D006420:Hemeproteins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D010100:Oxygen