Molecular basis of the allosteric mechanism of cAMP in the regulatory PKA subunit

The second messenger cyclic Adenosine MonoPosphate (cAMP) mediates many biological process by interacting with structurally conserved nucleotide binding domains (cNBD's). Here, we use molecular dynamics simulations on RIIβ-PKA, one of the best characterized members of the cNBD family, in presence and absence of cAMP. The results of our calculations are filly consistent with the available experimental data and suggest that the key factor of the cAMP allosteric mechanism in c NBDS's is the increased flexibility of the protein upon ligand release along with a mechanical coupling between helical segments. In addition, our calculations provide a rationale for the experimentally observed cAMP selective binding to PKA. © 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.