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PMID:15692043

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Citation

Kim, C, Xuong, NH and Taylor, SS (2005) Crystal structure of a complex between the catalytic and regulatory (RIalpha) subunits of PKA. Science 307:690-6

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 (RIalpha) 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 RIalpha. These residues compete with cAMP for the phosphate binding cassette in RIalpha. In contrast to the catalytic subunit, RIalpha undergoes major conformational changes when the complex is compared with cAMP-bound RIalpha. The inhibitor sequence docks to the active site, whereas the linker, also disordered in free RIalpha, 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.

Links

PubMed Online version:10.1126/science.1104607

Keywords

Binding Sites; Catalytic Domain; Crystallization; Crystallography, X-Ray; Cyclic AMP/metabolism; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases/chemistry; Cyclic AMP-Dependent Protein Kinases/metabolism; Enzyme Activation; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Phosphorylation; Protein Binding; Protein Conformation; Protein Structure, Quaternary; Protein Structure, Secondary; Protein Structure, Tertiary; Tryptophan/chemistry; Tyrosine/chemistry

Significance

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