Cyclic AMP Receptor protein (CRP) regulates transcription initiation in E. coli. The ligand and DNA binding data yields the following results: (1) There are two different types of cAMP binding sites; weak and strong. (2) CRP-DNA-cAMP is the active form of all CRP conformers and this complex prefers to form from CRP-DNA rather than CRP-cAMP form. (3) Binding of additional cAMP(s) to CRP-DNA-cAMP complex greatly reduces DNA binding affinity. (4) Variants showed that ribose moiety of cAMP is important to transmit the signal to the DNA binding domain to activate specific DNA binding. (5) Deconvolution of DNA binding data leads us to propose a model for cAMP's role in transcription initiation process.