# The World of Cyclic Dinucleotides in Bacterial Behavior
### GGDEF Domain Structure and Catalysis  
GGDEF structure and structural similarities with other protein domains. The GGDEF domain has an overall structure composed of a central five-stranded \(\beta\) sheet surrounded by five \(\alpha\) helices [70] and one hairpin (Figure 1B,C). The GGDEF domain has structural similarities to three other catalytic domains: (a) the class III adenylate and guanylate cyclase catalytic domains (Guanylate_cyc, PF00211), (b) the GTP cyclohydrolase III (GCH_III, PF05165), and (c) the palm domain of family Y DNA polymerases, such as IMS domain-impB/mucB/samB family domain, PF00817) (Figure 1). All of these families have a similar structural core composed by a \(\beta\)-\(\alpha\)-\(\beta\)-\(\beta\)-\(\alpha\)-\(\beta\)-\(\alpha\)-\(\beta\) topology (Figure 1B), which contains the Alpha-beta Plait topology (\(\beta\)-\(\alpha\)-\(\beta\)-\(\beta\)-\(\alpha\)-\(\beta\)), as defined by the CATH database [71]. The specific version of the Alpha-beta Plait topology embedded in this group is better known as the RNA Recognition Motif-like fold (RRM-like fold) and corresponds to the so-called \"palm domain\"shared by archaeo-eukaryotic primases, reverse transcriptases, viral RNA-dependent RNA polymerases and families A, B, and Y of DNA polymerases [72]. The catalytic domains of class III adenylyl cyclase (AC) and guanylyl cyclase (GC) are involved in the conversion of adenosine triphosphate (ATP) to 3'-5' cyclic AMP (cAMP) and in the conversion of guanosine triphosphate (GTP) to 3'-5' cyclic GMP (cGMP), respectively (Figure 1C) [73; 74]. Class III AC and GC are well characterized: they are widely present in eukaryotic and prokaryotic cells and perform important function in many human tissues, being involved in signal transduction [66]. The GCH_III domain (GTP cyclohydrolase III) catalyzes the conversion of GTP to 2-amino-5-formylamino-6-ribosylamino-4(3\(H\))-pyrimidininone 5'-phosphate (FAPy) [75]. GCH III catalyzes two modifications on the GTP molecule that involve two hydrolysis reactions, one at the base (a cyclohydrolase activity) and another in the phosphodieser bond (phosphotransferase reaction) that causes the release of a pyrophosphate molecule [75] (Figure 1C). Palm domains recognized by the IMS model of the Pfam database are the catalytic domains of DNA polymerases such as prokaryotic DNA polymerase IV and eukaryotic DNA polymerases eta and kappa [76]. All of them are Family Y DNA polymerases involved in DNA repair and exhibit error-prone behavior [77]. In these enzymes, the palm domain has deoxynucleotidyltransferase activity (Figure 1C). Given their conserved structural similarity to GGDEF domains, the class III adenylyl/guanylyl cyclases (AC/GC), GTP cyclohydrolase III, and the palm domain of DNA polymerases have been shown to be ancient homologous domains [78] that evolved from a common ancestor to perform different biological functions while preserving some core similarities such as: binding of nucleotides or deoxynucleotides and release pyrophosphate or phosphate during the enzymatic reaction course. Figure 1: Structural similarities between GGDEF (**GG[D/E][E/D]F** conserved sequence motif) domains and adenylate/guanylate cyclase, GTP (guanosine triphosphate) cyclohydrolase III and RRM-like palm  
domain of DNA polymerases. (**A**) dendrogram showing structures similar to GGDEF domain made with the Dali server [79] (query: PleD PDBID: 2V0N). Each domain is colored with different colors and the PDBID_chain and the Pfam name are shown for each branch. The conserved fold found in most of these structures is shown in brown, panel (**B**), overlaid on the GGDEF domain of PleD topology. (**C**) structural superposition of GGDEF domain of PleD (PDBID: 2 VON) with the other domains shown in the dendrogram (panel A), using the same colors to represent each domain. At the bottom of each structural alignment, the domain's name and the PDBID code is shown, as well as the chemical reaction performed.