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PDBsum entry 4jva
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Transferase/transferase inhibitor
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PDB id
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4jva
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Crystal structure of riibeta(108-402) bound to he33, a n6 di-propyl substituted camp analog
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Structure:
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Camp-dependent protein kinase type ii-beta regulatory subunit. Chain: a. Fragment: riibeta(108-402) of camp-dependent protein kinase. Engineered: yes. Mutation: yes
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Source:
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Rattus norvegicus. Brown rat,rat,rats. Organism_taxid: 10116. Gene: prkar2b. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.50Å
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R-factor:
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0.238
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R-free:
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0.278
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Authors:
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S.H.J.Brown,C.Y.Cheng,A.S.Saldanha,J.Wu,H.Cottam,B.Sankaran, S.S.Taylor
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Key ref:
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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:
DOI:
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Date:
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25-Mar-13
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Release date:
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18-Sep-13
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PROCHECK
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Headers
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References
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P12369
(KAP3_RAT) -
cAMP-dependent protein kinase type II-beta regulatory subunit from Rattus norvegicus
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Seq:
Struc:
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416 a.a.
264 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Acs Chem Biol
8:2164-2172
(2013)
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PubMed id:
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Implementing fluorescence anisotropy screening and crystallographic analysis to define PKA isoform-selective activation by cAMP analogs.
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S.H.Brown,
C.Y.Cheng,
S.A.Saldanha,
J.Wu,
H.B.Cottam,
B.Sankaran,
S.S.Taylor.
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ABSTRACT
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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.
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