PDBsum entry 4jv4

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Transferase/transferase inhibitor PDB id
Protein chain
261 a.a.
1OR ×2
PDB id:
Name: Transferase/transferase inhibitor
Title: Crystal structure of rialpha(91-379) bound to he33, a n6 di- substituted camp analog
Structure: Camp-dependent protein kinase type i-alpha regula subunit. Chain: a. Fragment: rialpha (93-380). Engineered: yes. Mutation: yes
Source: Bos taurus. Bovine,cow,domestic cattle,domestic cow. Organism_taxid: 9913. Gene: prkar1a. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.95Å     R-factor:   0.222     R-free:   0.286
Authors: S.H.J.Brown,C.Y.Cheng,A.S.Saldanha,J.Wu,H.Cottam,B.Sankaran, S.S.Taylor
Key ref: S.H.Brown et al. (2013). Implementing fluorescence anisotropy screening and crystallographic analysis to define PKA isoform-selective activation by cAMP analogs. ACS Chem Biol, 8, 2164-2172. PubMed id: 23978166 DOI: 10.1021/cb400247t
25-Mar-13     Release date:   18-Sep-13    
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Protein chain
Pfam   ArchSchema ?
P00514  (KAP0_BOVIN) -  cAMP-dependent protein kinase type I-alpha regulatory subunit
380 a.a.
261 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cAMP-dependent protein kinase complex   1 term 
  Biological process     regulation of protein phosphorylation   1 term 
  Biochemical function     cAMP-dependent protein kinase regulator activity     1 term  


DOI no: 10.1021/cb400247t ACS Chem Biol 8:2164-2172 (2013)
PubMed id: 23978166  
Implementing fluorescence anisotropy screening and crystallographic analysis to define PKA isoform-selective activation by cAMP analogs.
S.H.Brown, C.Y.Cheng, S.A.Saldanha, J.Wu, H.B.Cottam, B.Sankaran, S.S.Taylor.
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, RIα, RIβ, RIIα, and RIIβ. 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 RIα holoenzymes are selectively activated by C8-substituted analogs and RIIβ holoenzymes by N6-substituted analogs, where HE33 is the most prominent RII activator. We also solved the crystal structures of both RIα and RIIβ bound to HE33. The RIIβ structure shows the bulky aliphatic substituent of HE33 is fully encompassed by a pocket comprising of hydrophobic residues. RIα 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 RIIβ, but not RIα, 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.