4jv4

Crystal Structure of RIalpha(91-379) bound to HE33, a N6 di-propyl substituted cAMP analog

spinqualitylabelsall models 4jv4, resolution 2.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4jv4 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: 1OR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KAP0_BOVIN Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Publication Abstract from PubMed Cyclic AMP (cAMP) is a ubiquitous second messenger that regulates many proteins, most notably cAMP-dependent protein kinase (PKA). PKA holoenzymes (comprised of two catalytic (C) and two regulatory (R) subunits) regulate a wide variety of cellular processes, and its functional diversity is amplified by the presence of four R-subunit isoforms, RIalpha, RIbeta, RIIalpha, and RIIbeta. Although these isoforms all respond to cAMP, they are functionally nonredundant and exhibit different biochemical properties. In order to understand the functional differences between these isoforms, we screened cAMP derivatives for their ability to selectively activate RI and RII PKA holoenzymes using a fluorescence anisotropy assay. Our results indicate that RIalpha holoenzymes are selectively activated by C8-substituted analogs and RIIbeta holoenzymes by N6-substituted analogs, where HE33 is the most prominent RII activator. We also solved the crystal structures of both RIalpha and RIIbeta bound to HE33. The RIIbeta structure shows the bulky aliphatic substituent of HE33 is fully encompassed by a pocket comprising of hydrophobic residues. RIalpha lacks this hydrophobic lining in Domain A, and the side chains are displaced to accommodate the HE33 dipropyl groups. Comparison between cAMP-bound structures reveals that RIIbeta, but not RIalpha, contains a cavity near the N6 site. This study suggests that the selective activation of RII over RI isoforms by N6 analogs is driven by the spatial and chemical constraints of Domain A and paves the way for the development of potent noncyclic nucleotide activators to specifically target PKA iso-holoenyzmes. Implementing Fluorescence Anisotropy Screening and Crystallographic Analysis to Define PKA Isoform-Selective Activation by cAMP Analogs.,Brown SH, Cheng CY, Saldanha SA, Wu J, Cottam HB, Sankaran B, Taylor SS ACS Chem Biol. 2013 Sep 10. PMID:23978166 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also CAMP-dependent protein kinase CAMP-dependent protein kinase 3D structures

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