title: Aspartate 102 in the heme domain of soluble guanylyl cyclase has a key role in NO activation.
abstract: Nitric oxide (NO) is involved in the physiology and pathophysiology of the cardiovascular and neuronal systems via activation of soluble guanylyl cyclase (sGC), a heme-containing heterodimer. Recent structural studies have allowed a better understanding of the residues that dictate the affinity and binding of NO to the heme and the resulting breakage of the bond between the heme iron and histidine 105 (H105) of the β subunit of sGC. Still, it is unknown how the breakage of the iron-His bond translates into NO-dependent increased catalysis. Structural studies on homologous H-NOX domains in various states pointed to a role for movement of the H105 containing αF helix. Our modeling of the heme-binding domain highlighted conserved residues in the vicinity of H105 that could potentially regulate the extent to which the αF helix shifts and/or propagate the activation signal once the covalent bond with H105 has been broken. These include a direct interaction of αF helix residue aspartate 102 (D102) with the backbone nitrogen of F120. Mutational analysis of this region points to an essential role of the interactions in the vicinity of H105 for heme stability and identifies D102 as having a key role in NO activation following breakage of the iron-His bond.
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School/UMDNJ, Newark, NJ 07103, USA.
authors.forename: Padmamalini
authors.initials: P
authors.lastname: Baskaran
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Heckler
authors.forename: Focco
authors.initials: F
authors.lastname: van den Akker
authors.forename: Annie
authors.initials: A
authors.lastname: Beuve
mesh_terms: D000409:Alanine / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006418:Heme / Q000737:chemistry* / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009569:Nitric Oxide / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D000071756:Soluble Guanylyl Cyclase
chemical_list: D007191:Indazoles; D021122:Protein Subunits; D018160:Receptors, Cytoplasmic and Nuclear; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D001224:Aspartic Acid; D009569:Nitric Oxide; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D000409:Alanine