2QCS: A Complex Structure Between The Catalytic And Regulatory Subunit Of Protein Kinase A That Represents The Inhibited State

Citation:
Abstract
Protein kinase A (PKA) holoenzyme is one of the major receptors for cyclic adenosine monophosphate (cAMP), where an extracellular stimulus is translated into a signaling response. We report here the structure of a complex between the PKA catalytic subunit and a mutant RI regulatory subunit, RIalpha(91-379:R333K), containing both cAMP-binding domains. Upon binding to the catalytic subunit, RI undergoes a dramatic conformational change in which the two cAMP-binding domains uncouple and wrap around the large lobe of the catalytic subunit. This large conformational reorganization reveals the concerted mechanism required to bind and inhibit the catalytic subunit. The structure also reveals a holoenzyme-specific salt bridge between two conserved residues, Glu261 and Arg366, that tethers the two adenine capping residues far from their cAMP-binding sites. Mutagenesis of these residues demonstrates their importance for PKA activation. Our structural insights, combined with the mutagenesis results, provide a molecular mechanism for the ordered and cooperative activation of PKA by cAMP.
PDB ID: 2QCSDownload
MMDB ID: 60553
PDB Deposition Date: 2007/6/19
Updated in MMDB: 2007/11
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Mus musculus
Similar Structures:
Biological Unit for 2QCS: dimeric; determined by author and by software (PISA)
Molecular Components in 2QCS
Label Count Molecule
Proteins (2 molecules)
1
Camp-dependent Protein Kinase, Alpha-catalytic Subunit(Gene symbol: Prkaca)
Molecule annotation
1
Camp-dependent Protein Kinase Type I-alpha Regulatory Subunit(Gene symbol: PRKAR1A)
Molecule annotation
Chemicals (14 molecules)
1
2
2
6
3
1
4
1
5
1
6
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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