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.
Keywords
Molecular models presented in Figs. 3–9 were generated and drawn with the program suite SYBYL X2 (Certara LP, Princeton, NJ, USA).
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Dove, S. (2015). Mammalian Nucleotidyl Cyclases and Their Nucleotide Binding Sites. In: Seifert, R. (eds) Non-canonical Cyclic Nucleotides. Handbook of Experimental Pharmacology, vol 238. Springer, Cham. https://doi.org/10.1007/164_2015_34
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DOI: https://doi.org/10.1007/164_2015_34
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