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PDBsum entry 1cx4
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Signaling protein
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PDB id
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1cx4
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Contents |
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* Residue conservation analysis
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DOI no:
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Structure
9:73-82
(2001)
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PubMed id:
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Molecular basis for regulatory subunit diversity in cAMP-dependent protein kinase: crystal structure of the type II beta regulatory subunit.
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T.C.Diller,
Madhusudan,
N.H.Xuong,
S.S.Taylor.
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ABSTRACT
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BACKGROUND: Cyclic AMP binding domains possess common structural features yet
are diversely coupled to different signaling modules. Each cAMP binding domain
receives and transmits a cAMP signal; however, the signaling networks differ
even within the same family of regulatory proteins as evidenced by the
long-standing biochemical and physiological differences between type I and type
II regulatory subunits of cAMP-dependent protein kinase. RESULTS: We report the
first type II regulatory subunit crystal structure, which we determined to 2.45
A resolution and refined to an R factor of 0.176 with a free R factor of 0.198.
This new structure of the type II beta regulatory subunit of cAMP-dependent
protein kinase demonstrates that the relative orientations of the two tandem
cAMP binding domains are very different in the type II beta as compared to the
type I alpha regulatory subunit. Each structural unit for binding cAMP contains
the highly conserved phosphate binding cassette that can be considered the
"signature" motif of cAMP binding domains. This motif is coupled to
nonconserved regions that link the cAMP signal to diverse structural and
functional modules. CONCLUSIONS: Both the diversity and similarity of cAMP
binding sites are demonstrated by this new type II regulatory subunit structure.
The structure represents an intramolecular paradigm for the cooperative triad
that links two cAMP binding sites through a domain interface to the catalytic
subunit of cAMP-dependent protein kinase. The domain interface surface is
created by the binding of only one cAMP molecule and is enabled by amino acid
sequence variability within the peptide chain that tethers the two domains
together.
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Selected figure(s)
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Figure 4.
Figure 4. Hydrogen Bonds Surrounding cAMPThe network of
conserved and nonconserved hydrogen bonds surrounding the two
cAMP binding sites of RIIb.(a) Binding site A.(b) Binding site
B. Cyclic AMP molecules are rendered as balls and sticks with
gray for carbon, blue for nitrogen, red for oxygen, and purple
for the phosphorous atom. Hydrogen bonding is represented by
dashed lines. Water oxygen atoms are illustrated as ovals with
gradient shading and the uniquely identifying three-digit
numeral assigned by the PDB file 1cx4. Tan-shaded boxes signify
secondary structural elements identified in Figure 3; the labels
for these boxes are either red for b strands or green for a
helices. The regions encompassed by yellow lie within the
conserved phosphate binding cassette. Amino acid residues with
more than one hydrogen-bonding atom are boxed and labeled in
either blue for invariant residues or black for nonconserved
residues
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2001,
9,
73-82)
copyright 2001.
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Figure was
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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J.H.Lee,
S.Li,
T.Liu,
S.Hsu,
C.Kim,
V.L.Woods,
and
D.E.Casteel
(2011).
The amino terminus of cGMP-dependent protein kinase Iβ increases the dynamics of the protein's cGMP-binding pockets.
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Int J Mass Spectrom,
302,
44-52.
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N.Wurtz,
C.Chapus,
J.Desplans,
and
D.Parzy
(2011).
cAMP-dependent protein kinase from Plasmodium falciparum: an update.
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Parasitology,
138,
1.
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J.Rinaldi,
J.Wu,
J.Yang,
C.Y.Ralston,
B.Sankaran,
S.Moreno,
and
S.S.Taylor
(2010).
Structure of yeast regulatory subunit: a glimpse into the evolution of PKA signaling.
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Structure,
18,
1471-1482.
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PDB code:
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T.J.Sjoberg,
A.P.Kornev,
and
S.S.Taylor
(2010).
Dissecting the cAMP-inducible allosteric switch in protein kinase A RIalpha.
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Protein Sci,
19,
1213-1221.
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PDB code:
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S.Naviglio,
M.Caraglia,
A.Abbruzzese,
E.Chiosi,
D.Di Gesto,
M.Marra,
M.Romano,
A.Sorrentino,
L.Sorvillo,
A.Spina,
and
G.Illiano
(2009).
Protein kinase A as a biological target in cancer therapy.
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Expert Opin Ther Targets,
13,
83-92.
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S.Schünke,
M.Stoldt,
K.Novak,
U.B.Kaupp,
and
D.Willbold
(2009).
Solution structure of the Mesorhizobium loti K1 channel cyclic nucleotide-binding domain in complex with cAMP.
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EMBO Rep,
10,
729-735.
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PDB code:
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T.T.Aye,
S.Mohammed,
H.W.van den Toorn,
T.A.van Veen,
M.A.van der Heyden,
A.Scholten,
and
A.J.Heck
(2009).
Selectivity in enrichment of cAMP-dependent protein kinase regulatory subunits type I and type II and their interactors using modified cAMP affinity resins.
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Mol Cell Proteomics,
8,
1016-1028.
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A.P.Kornev,
S.S.Taylor,
and
L.F.Ten Eyck
(2008).
A generalized allosteric mechanism for cis-regulated cyclic nucleotide binding domains.
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PLoS Comput Biol,
4,
e1000056.
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H.Rehmann,
E.Arias-Palomo,
M.A.Hadders,
F.Schwede,
O.Llorca,
and
J.L.Bos
(2008).
Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B.
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Nature,
455,
124-127.
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PDB code:
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S.M.Harper,
H.Wienk,
R.W.Wechselberger,
J.L.Bos,
R.Boelens,
and
H.Rehmann
(2008).
Structural dynamics in the activation of Epac.
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J Biol Chem,
283,
6501-6508.
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S.S.Taylor,
C.Kim,
C.Y.Cheng,
S.H.Brown,
J.Wu,
and
N.Kannan
(2008).
Signaling through cAMP and cAMP-dependent protein kinase: diverse strategies for drug design.
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Biochim Biophys Acta,
1784,
16-26.
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W.N.van Egmond,
A.Kortholt,
K.Plak,
L.Bosgraaf,
S.Bosgraaf,
I.Keizer-Gunnink,
and
P.J.van Haastert
(2008).
Intramolecular Activation Mechanism of the Dictyostelium LRRK2 Homolog Roco Protein GbpC.
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J Biol Chem,
283,
30412-30420.
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E.M.Rubenstein,
and
M.C.Schmidt
(2007).
Mechanisms regulating the protein kinases of Saccharomyces cerevisiae.
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Eukaryot Cell,
6,
571-583.
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H.Rehmann,
A.Wittinghofer,
and
J.L.Bos
(2007).
Capturing cyclic nucleotides in action: snapshots from crystallographic studies.
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Nat Rev Mol Cell Biol,
8,
63-73.
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J.W.Scott,
F.A.Ross,
J.K.Liu,
and
D.G.Hardie
(2007).
Regulation of AMP-activated protein kinase by a pseudosubstrate sequence on the gamma subunit.
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EMBO J,
26,
806-815.
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J.Wu,
S.H.Brown,
S.von Daake,
and
S.S.Taylor
(2007).
PKA type IIalpha holoenzyme reveals a combinatorial strategy for isoform diversity.
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Science,
318,
274-279.
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PDB code:
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N.Kannan,
J.Wu,
G.S.Anand,
S.Yooseph,
A.F.Neuwald,
C.J.Venter,
and
S.S.Taylor
(2007).
Evolution of allostery in the cyclic nucleotide binding module.
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Genome Biol,
8,
R264.
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D.Vigil,
J.H.Lin,
C.A.Sotriffer,
J.K.Pennypacker,
J.A.McCammon,
and
S.S.Taylor
(2006).
A simple electrostatic switch important in the activation of type I protein kinase A by cyclic AMP.
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Protein Sci,
15,
113-121.
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J.Gullingsrud,
C.Kim,
S.S.Taylor,
and
J.A.McCammon
(2006).
Dynamic binding of PKA regulatory subunit RI alpha.
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Structure,
14,
141-149.
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J.Trewhella
(2006).
Structural themes and variations in protein kinase A as seen by small-angle scattering and neutron contrast variation.
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Eur Biophys J,
35,
585-589.
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K.K.Dao,
K.Teigen,
R.Kopperud,
E.Hodneland,
F.Schwede,
A.E.Christensen,
A.Martinez,
and
S.O.Døskeland
(2006).
Epac1 and cAMP-dependent protein kinase holoenzyme have similar cAMP affinity, but their cAMP domains have distinct structural features and cyclic nucleotide recognition.
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J Biol Chem,
281,
21500-21511.
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M.Berrera,
S.Pantano,
and
P.Carloni
(2006).
cAMP Modulation of the cytoplasmic domain in the HCN2 channel investigated by molecular simulations.
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Biophys J,
90,
3428-3433.
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M.Y.Galperin
(2006).
Structural classification of bacterial response regulators: diversity of output domains and domain combinations.
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J Bacteriol,
188,
4169-4182.
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R.L.Brown,
T.Strassmaier,
J.D.Brady,
and
J.W.Karpen
(2006).
The pharmacology of cyclic nucleotide-gated channels: emerging from the darkness.
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Curr Pharm Des,
12,
3597-3613.
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C.Hahnefeld,
D.Moll,
M.Goette,
and
F.W.Herberg
(2005).
Rearrangements in a hydrophobic core region mediate cAMP action in the regulatory subunit of PKA.
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Biol Chem,
386,
623-631.
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C.Kim,
N.H.Xuong,
and
S.S.Taylor
(2005).
Crystal structure of a complex between the catalytic and regulatory (RIalpha) subunits of PKA.
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Science,
307,
690-696.
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PDB codes:
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D.Bridges,
M.E.Fraser,
and
G.B.Moorhead
(2005).
Cyclic nucleotide binding proteins in the Arabidopsis thaliana and Oryza sativa genomes.
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BMC Bioinformatics,
6,
6.
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D.Vigil,
D.K.Blumenthal,
S.S.Taylor,
and
J.Trewhella
(2005).
The conformationally dynamic C helix of the RIalpha subunit of protein kinase A mediates isoform-specific domain reorganization upon C subunit binding.
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J Biol Chem,
280,
35521-35527.
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M.Eiting,
G.Hagelüken,
W.D.Schubert,
and
D.W.Heinz
(2005).
The mutation G145S in PrfA, a key virulence regulator of Listeria monocytogenes, increases DNA-binding affinity by stabilizing the HTH motif.
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Mol Microbiol,
56,
433-446.
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PDB codes:
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E.C.Young,
and
N.Krougliak
(2004).
Distinct structural determinants of efficacy and sensitivity in the ligand-binding domain of cyclic nucleotide-gated channels.
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J Biol Chem,
279,
3553-3562.
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G.M.Clayton,
W.R.Silverman,
L.Heginbotham,
and
J.H.Morais-Cabral
(2004).
Structural basis of ligand activation in a cyclic nucleotide regulated potassium channel.
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Cell,
119,
615-627.
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PDB codes:
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J.Wu,
S.Brown,
N.H.Xuong,
and
S.S.Taylor
(2004).
RIalpha subunit of PKA: a cAMP-free structure reveals a hydrophobic capping mechanism for docking cAMP into site B.
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Structure,
12,
1057-1065.
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PDB code:
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K.M.Zawadzki,
and
S.S.Taylor
(2004).
cAMP-dependent protein kinase regulatory subunit type IIbeta: active site mutations define an isoform-specific network for allosteric signaling by cAMP.
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J Biol Chem,
279,
7029-7036.
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V.O.Nikolaev,
M.Bünemann,
L.Hein,
A.Hannawacker,
and
M.J.Lohse
(2004).
Novel single chain cAMP sensors for receptor-induced signal propagation.
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J Biol Chem,
279,
37215-37218.
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W.T.Heller,
D.Vigil,
S.Brown,
D.K.Blumenthal,
S.S.Taylor,
and
J.Trewhella
(2004).
C subunits binding to the protein kinase A RI alpha dimer induce a large conformational change.
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J Biol Chem,
279,
19084-19090.
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A.E.Christensen,
F.Selheim,
J.de Rooij,
S.Dremier,
F.Schwede,
K.K.Dao,
A.Martinez,
C.Maenhaut,
J.L.Bos,
H.G.Genieser,
and
S.O.Døskeland
(2003).
cAMP analog mapping of Epac1 and cAMP kinase. Discriminating analogs demonstrate that Epac and cAMP kinase act synergistically to promote PC-12 cell neurite extension.
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J Biol Chem,
278,
35394-35402.
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H.Rehmann,
A.Rueppel,
J.L.Bos,
and
A.Wittinghofer
(2003).
Communication between the regulatory and the catalytic region of the cAMP-responsive guanine nucleotide exchange factor Epac.
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J Biol Chem,
278,
23508-23514.
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H.Rehmann,
B.Prakash,
E.Wolf,
A.Rueppel,
J.de Rooij,
J.L.Bos,
and
A.Wittinghofer
(2003).
Structure and regulation of the cAMP-binding domains of Epac2.
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Nat Struct Biol,
10,
26-32.
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PDB code:
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J.L.Bos
(2003).
Epac: a new cAMP target and new avenues in cAMP research.
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Nat Rev Mol Cell Biol,
4,
733-738.
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K.M.Zawadzki,
C.P.Pan,
M.D.Barkley,
D.Johnson,
and
S.S.Taylor
(2003).
Endogenous tryptophan residues of cAPK regulatory subunit type IIbeta reveal local variations in environments and dynamics.
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Proteins,
51,
552-561.
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K.M.Zawadzki,
Y.Hamuro,
J.S.Kim,
S.Garrod,
D.D.Stranz,
S.S.Taylor,
and
V.L.Woods
(2003).
Dissecting interdomain communication within cAPK regulatory subunit type IIbeta using enhanced amide hydrogen/deuterium exchange mass spectrometry (DXMS).
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Protein Sci,
12,
1980-1990.
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R.Chen,
and
J.C.Lee
(2003).
Functional roles of loops 3 and 4 in the cyclic nucleotide binding domain of cyclic AMP receptor protein from Escherichia coli.
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J Biol Chem,
278,
13235-13243.
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C.S.Tung,
D.A.Walsh,
and
J.Trewhella
(2002).
A structural model of the catalytic subunit-regulatory subunit dimeric complex of the cAMP-dependent protein kinase.
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J Biol Chem,
277,
12423-12431.
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PDB codes:
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J.M.Goldberg,
L.Bosgraaf,
P.J.Van Haastert,
and
J.L.Smith
(2002).
Identification of four candidate cGMP targets in Dictyostelium.
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Proc Natl Acad Sci U S A,
99,
6749-6754.
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M.E.Meima,
R.M.Biondi,
and
P.Schaap
(2002).
Identification of a novel type of cGMP phosphodiesterase that is defective in the chemotactic stmF mutants.
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Mol Biol Cell,
13,
3870-3877.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
