title: Mammalian Nucleotidyl Cyclases and Their Nucleotide Binding Sites.
abstract: Mammalian membranous and soluble adenylyl cyclases (mAC, sAC) and soluble guanylyl cyclases (sGC) generate cAMP and cGMP from ATP and GTP, respectively, as substrates. mACs (nine human isoenzymes), sAC, and sGC differ in their overall structures owing to specific membrane-spanning and regulatory domains but consist of two similarly folded catalytic domains C1 and C2 with high structure-based homology between the cyclase species. Comparison of available crystal structures - VC1:IIC2 (a construct of domains C1a from dog mAC5 and C2a from rat mAC2), human sAC and sGC, mostly in complex with substrates, substrate analogs, inhibitors, metal ions, and/or modulators - reveals that especially the nucleotide binding sites are closely related. An evolutionarily well-conserved catalytic mechanism is based on common binding modes, interactions, and structural transformations, including the participation of two metal ions in catalysis. Nucleobase selectivity relies on only few mutations. Since in all cases the nucleoside moiety is embedded in a relatively spacious cavity, mACs, sAC, and sGC are rather promiscuous and bind nearly all purine and pyrimidine nucleotides, including CTP and UTP, and many of their derivatives as inhibitors with often high affinity. By contrast, substrate specificity of mammalian adenylyl and guanylyl cyclases is high due to selective dynamic rearrangements during turnover.
authors.affiliation: University of Regensburg, Institute of Pharmacy, Regensburg, 93040, Germany. Stefan.Dove@chemie.uni-regensburg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dove
mesh_terms: D000262:Adenylyl Cyclases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D015290:Second Messenger Systems; D000071756:Soluble Guanylyl Cyclase / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000242:Cyclic AMP; C579271:ADCY10 protein, human; D000262:Adenylyl Cyclases; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
keywords: Binding modes; Inhibitors; Membranous adenylyl cyclase; Soluble adenylyl cyclase; Soluble guanylyl cyclase; Structure; Substrates