# The World of Cyclic Dinucleotides in Bacterial Behavior
## 3 Cyclic Dinucleotide Receptors
The residues highlighted in yellow are involved with direct interaction with the ligand, those in green are involved with interaction with the ligand via magnesium ions, and those in cyan interact via water molecules; (**B**) structural superposition of STING proteins (domain TMEM173) in complex with different CDNs bound at the same protein interface. The ligands are colored by element: nitrogen atoms are in dark blue and oxygens are in red. Carbons are colored according to the ligand: 3'-5' \(c\)-di-GMP in orange; 2'-3' cGAMP in blue, 3'-5' c-di-AMP in purple and; 3'-5' cGAMP in green; (**C**) residues involved in interactions with the different ligands are the same one highlighted in panel (**A**). The residues are colored by element, with carbon in white, nitrogen in dark blue, and oxygen in red, while the ligands are colored as described in panel (**B**). Water molecules are shown as blue spheres, while magnesium cations are shown as green spheres. (**D**) multiple sequence alignment of the PiIZ domains that had their structures solved in complex with c-di-GMP molecules. Residues highlighted in yellow are involved in interactions with the ligand. The secondary structure elements shown belong to the PiIZ domain of YcgR from _E. coli_ (PDBID: 5Y6F). The motifs conserved within PiIZ members are placed in red boxes; (**E**) some domain organizations found in proteins containing PiIZ domains (Alg44, BcsA, and YcgR) and their related functions; (**F**) structural representation of a PiIZ domain as a cartoon (PiIZ domain of YcgR, PDBID: 5Y6F). Residues belonging to the \"RoxCR\" motif are colored in orange, the \"DxSoxG\" motif is colored in blue, and the \(\beta\) strand 7 is colored in green. The dimeric c-di-GMP is shown as sticks. The interaction network presented in this figure is shown in more details in panel (**G**); (**H**) multiple sequence alignment of proteins containing degenerate EAL domains (PDBID: 4F48, 4 FOK, and 3 PJT) and a catalytic EAL domain (PDBID: 3 SY8) that had their structure solved in complex with monomeric c-di-GMP. The residues highlighted in yellow are involved with direct interactions with the ligand, those in green are involved with interactions with the ligand via magnesium ions. In the case of RocR, which has a catalytic EAL domain, the residues highlighted in salmon were experimentally demonstrated to be important for catalysis [123].The consensus \"EAL\" motif is placed in a red box; (**I**) interaction network of the binding site of a FinX degenerate EAL domain (PDBID: 4 FOK). Gray dotted lines represent hydrogen bonds. The residues and the c-di-GMP molecule are colored by element. The multiple sequence alignments were performed using the CLUSTAL W server [116]. Other important c-di-GMP receptors are proteins containing PiIZ domains (PF07238). PiIZ domains regulate twitching and swarming motility via the flagellar regulator YcgR protein [7], but proteins containing different domain architectures are related with other functions, such as the regulation of the synthesis of cellulose by BcsA in _Rhodobacter sphaeroides_, or chemotaxis by MapZ protein and alginate secretion by Alg44 to promote biofilm formation in _Pseudomonas aeruginosa_ (Figure 7E and Table 1). PiIZ domain is found associated with different domains that could be sensor domains, such as GAF, Cache, and PAS domains, and catalytic domains such as GGDEF, EAL, and Peptides_S8. Therefore, proteins containing PiIZ domain could be classified based on their domain architecture and function in different paralogous families [124; 125]. The Pfam database describes 221 different domain architectures containing PiIZ domains [89], showing the diversity of signaling networks in which c-di-GMP can be involved and have not yet been explored. It is interesting that two proteins containing PiIZ domains that are c-di-GMP receptors have been found to be involved in the production of different exopolysaccharideaderiates to produce bacterial biofilms: cellulose and alginate.