The residues in and in close proximity to the cAMP binding sites interact with a network of residues that are present in various locations throughout the protein. The binding of the cAMP causes a shift in the residues, which is transmitted through the network, causing a conformational change.

As of yet, the actual conformational changes that occur are not known, because the crystal structure of the holoenzyme R2C2 tetramer has not been solved. However, some of the networking interactions are known.

Interactions with Site A

In Site A, the region from Gly199-Ala210 make many contacts. Glu200 is an important residue in this region that makes several contacts. Besides interacting with the 2' OH of the ribose in cAMP, it hydrogen bonds to the NE1 of Trp260 and makes electrostatic contacts with Arg 241.
The Glu200 residue is also at the beginning of a one and a half turn helix. The majority of the unpaired amides in the beginning of the helix are capped by interactions with the side chains of proteins or by interactions with cAMP.

An example of this interaction is the alpha NH of Glu199. Glu199 is well conserved among the cAMP binding sites seen ( sites A & B, and the binding site in CAP) The alpha NH of Gly 199 hydrogen bonds to the 2'OH of the cAMP, the alpha NH of Glu200 bonds to the OE2 of its own side chain. The alpha NH of Ala202 hydrogen bonds to the equitorial oxygen of the phosphate in cAMP. The alpha NH of Leu203 hydrogen bonds to the alpha carbonyl of Leu201.

The network is shown in the above graphic, and makes it easier to see how cAMP can effect a conformational change. The actual conformational change has not been seen yet, but some idea can be gotten of how the binding of the cyclic AMP transmits a signal throughout the protein.