Crystal structure of a complex between the catalytic and regulatory (RIα) subunits of PKA

The 2.0-angstrom structure of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) catalytic subunit bound to a deletion mutant of a regulatory subunit (Rlalpha) defines a previously unidentified extended interface. The complex provides a molecular mechanism for inhibition of PKA and suggests how CAMP binding leads to activation. The interface defines the large lobe of the catalytic subunit as a stable scaffold where Tyr(247) in the G helix and Trp(196) in the phosphorylated activation loop serve as anchor points for binding Rlalpha. These residues compete with CAMP for the phosphate binding cassette in Rlalpha. In contrast to the catalytic subunit, Rlalpha undergoes major conformational changes when the complex is compared with CAMP-bound Rlalpha. The inhibitor sequence docks to the active site, whereas the linker, also disordered in free Rlalpha, folds across the extended interface. The beta barrel of CAMP binding domain A, which is the docking site for CAMP, remains largely intact in the complex, whereas the helical subdomain undergoes major reorganization.