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Science 307 (5710): 690-696

Copyright © 2005 by the American Association for the Advancement of Science

Crystal Structure of a Complex Between the Catalytic and Regulatory (RI{alpha}) Subunits of PKA

Choel Kim,1 Nguyen-Huu Xuong,1,2 Susan S. Taylor1,3,4*

Abstract: 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 (RI{alpha}) 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 Tyr247 in the G helix and Trp196 in the phosphorylated activation loop serve as anchor points for binding RI{alpha}. These residues compete with cAMP for the phosphate binding cassette in RI{alpha}. In contrast to the catalytic subunit, RI{alpha} undergoes major conformational changes when the complex is compared with cAMP-bound RI{alpha}. The inhibitor sequence docks to the active site, whereas the linker, also disordered in free RI{alpha}, folds across the extended interface. The ß 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.

1 Department of Chemistry and Biochemistry, University of California, San Diego, CA 92093, USA.
2 Department of Physics and Biology, University of California, San Diego, CA 92093, USA.
3 Howard Hughes Medical Institute, University of California, San Diego, CA 92093, USA.
4 Department of Pharmacology, University of California, San Diego, CA 92093, USA.

* To whom correspondence should be addressed. E-mail: staylor{at}ucsd.edu

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