3iia | pdb_00003iia

Crystal structure of apo (91-244) RIa subunit of cAMP-dependent protein kinase

spinqualitylabelsall models 3iia, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3iia is a 1 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL Related: 1rgs, 1rl3, 1ne4, 1ne6, 3fhi Gene: PRKAR1A (Bos taurus) Resources: FirstGlance, OCA, RCSB, PDBsum Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed The regulatory (R) subunit of Protein Kinase A (PKA) serves to modulate the activity of PKA in a cAMP-dependent manner and exists in two distinct and structurally dissimilar, endpoint cAMP-bound 'B' and C-subunit-bound 'H'-conformations. Here we report X-ray crystallography showing surprisingly that the antagonist Rp-cAMPS-bound R-subunit crystallized in the 'H' conformation which was previously assumed to be induced only by C-subunit-binding. Interestingly the apo R-subunit crystallized in the 'B' conformation similar to the cAMP-bound protein. However amide hydrogen exchange mass spectrometry showed large differences between apo, agonist and antagonist-bound states of the R-subunit. Ion mobility mass spectrometry reveals the apo R-subunit is an ensemble of multiple conformations with collisional cross-sectional areas spanning both the agonist and antagonist-bound states. Thus contrary to earlier studies which explained the basis for cAMP action through 'induced fit', our results support a conformational selection model, where the ligand-free apo form of the R-subunit exists as an ensemble of both 'B' and 'H' conformations. While cAMP preferentially binds the 'B' conformation, Rp-cAMPS preferentially binds the 'H' conformation. This reveals the unique importance of the equatorial oxygen of the cyclic phosphate in mediating conformational transitions from 'H' to 'B' forms highlighting a novel approach for rational structure-based drug design. Ideal inhibitors such as Rp-cAMPS are those that preferentially 'select' inactive conformations of target proteins by satisfying all 'binding' constraints alone without inducing conformational changes necessary for activation. Cyclic AMP analog blocks kinase activation by stabilizing inactive conformation: Conformational selection highlights a new concept in allosteric inhibitor design.,Badireddy S, Yunfeng G, Ritchie M, Akamine P, Wu J, Kim CW, Taylor SS, Qingsong L, Swaminathan K, Anand GS Mol Cell Proteomics. 2010 Nov 16. PMID:21081668 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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