Cyclic AMP serves as an intracellular messenger in cells and regulates a variety of biological functions by transmitting information through proteins. These proteins of different functions all consist of a cAMP-binding motif, and the structure of this motif is highly conserved with an exception of the loop 3 and 4. In current study, cAMP receptor protein was employed as a model system to investigate the function of the two loops. The results indicated that the loop 3 involves in the intersubunits communication of CRP, whereas the loop 4 involves in cAMP binding and interdomains communication.