Abstract

In the molecular scheme of living organisms, adenosine 3′,5′-monophosphate (cyclic AMP or cAMP) has been a universal second messenger. In eukaryotic cells, the primary receptors for cAMP are the regulatory subunits of cAMP-dependent protein kinase. The crystal structure of a 1-91 deletion mutant of the type Iα regulatory subunit was refined to 2.8 Å resolution. Each of the two tandem cAMP binding domains provides an extensive network of hydrogen bonds that buries the cyclic phosphate and the ribose between two β strands that are linked by a short α helix. Each adenine base stacks against an aromatic ring that lies outside the β barrel. This structure provides a molecular basis for understanding how cAMP binds cooperatively to its receptor protein, thus mediating activation of the kinase.