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* Residue conservation analysis
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PDB id:
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Signaling protein
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Title:
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The crystal structure of a biologically active peptide (sigk) bound to a g protein beta:gamma heterodimer
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Structure:
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Guanine nucleotide-binding protein g(i)/g(s)/g(t) beta subunit 1. Chain: a. Synonym: transducin beta chain 1, g-protein beta1. Engineered: yes. Guanine nucleotide-binding protein g(i)/g(s)/g(o) gamma-2 subunit. Chain: b. Synonym: g gamma-i, g-protein gamma2.
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Source:
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Bos taurus. Cattle. Organism_taxid: 9913. Gene: gnb1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: gng2. Synthetic: yes. Other_details: the peptide was chemically synthesized. This sequence
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Biol. unit:
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Trimer (from
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Resolution:
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2.70Å
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R-factor:
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0.227
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R-free:
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0.287
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Authors:
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T.L.Davis,T.M.Bonacci,A.V.Smrcka,S.R.Sprang
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Key ref:
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T.L.Davis
et al.
(2005).
Structural and molecular characterization of a preferred protein interaction surface on G protein beta gamma subunits.
Biochemistry,
44,
10593-10604.
PubMed id:
DOI:
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Date:
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20-Sep-04
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Release date:
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09-Aug-05
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PROCHECK
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Headers
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References
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P62871
(GBB1_BOVIN) -
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 from Bos taurus
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Seq:
Struc:
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340 a.a.
339 a.a.
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DOI no:
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Biochemistry
44:10593-10604
(2005)
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PubMed id:
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Structural and molecular characterization of a preferred protein interaction surface on G protein beta gamma subunits.
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T.L.Davis,
T.M.Bonacci,
S.R.Sprang,
A.V.Smrcka.
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ABSTRACT
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G protein betagamma subunits associate with many binding partners in cellular
signaling cascades. In previous work, we used random-peptide phage display
screening to identify a diverse family of peptides that bound to a common
surface on Gbetagamma subunits and blocked a subset of Gbetagamma effectors.
Later studies showed that one of the peptides caused G protein activation
through a novel Gbetagamma-dependent, nucleotide exchange-independent mechanism.
Here we report the X-ray crystal structure of Gbeta(1)gamma(2) bound to this
peptide, SIGK (SIGKAFKILGYPDYD), at 2.7 A resolution. SIGK forms a helical
structure that binds the same face of Gbeta(1) as the switch II region of
Galpha. The interaction interface can be subdivided into polar and nonpolar
interfaces that together contain a mixture of binding determinants that may be
responsible for the ability of this surface to recognize multiple protein
partners. Systematic mutagenic analysis of the peptide-Gbeta(1) interface
indicates that distinct sets of amino acids within this interface are required
for binding of different peptides. Among these unique amino acid interactions,
specific electrostatic binding contacts within the polar interface are required
for peptide-mediated subunit dissociation. The data provide a mechanistic basis
for multiple target recognition by Gbetagamma subunits with diverse functional
interactions within a common interface and suggest that pharmacological
targeting of distinct regions within this interface could allow for selective
manipulation of Gbetagamma-dependent signaling pathways.
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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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M.S.Park,
A.V.Smrcka,
and
H.A.Stern
(2011).
Conformational flexibility and binding interactions of the G protein βγ heterodimer.
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Proteins,
79,
518-527.
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R.Eglen,
and
T.Reisine
(2011).
Drug discovery and the human kinome: recent trends.
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Pharmacol Ther,
130,
144-156.
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A.V.Smrcka,
N.Kichik,
T.Tarragó,
M.Burroughs,
M.S.Park,
N.K.Itoga,
H.A.Stern,
B.M.Willardson,
and
E.Giralt
(2010).
NMR analysis of G-protein betagamma subunit complexes reveals a dynamic G(alpha)-Gbetagamma subunit interface and multiple protein recognition modes.
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Proc Natl Acad Sci U S A,
107,
639-644.
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C.U.Stirnimann,
E.Petsalaki,
R.B.Russell,
and
C.W.Müller
(2010).
WD40 proteins propel cellular networks.
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Trends Biochem Sci,
35,
565-574.
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J.R.England,
J.Huang,
M.J.Jennings,
R.D.Makde,
and
S.Tan
(2010).
RCC1 uses a conformationally diverse loop region to interact with the nucleosome: a model for the RCC1-nucleosome complex.
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J Mol Biol,
398,
518-529.
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K.K.Jernigan,
C.S.Cselenyi,
C.A.Thorne,
A.J.Hanson,
E.Tahinci,
N.Hajicek,
W.M.Oldham,
L.A.Lee,
H.E.Hamm,
J.R.Hepler,
T.Kozasa,
M.E.Linder,
and
E.Lee
(2010).
Gbetagamma activates GSK3 to promote LRP6-mediated beta-catenin transcriptional activity.
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Sci Signal,
3,
ra37.
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M.Aittaleb,
C.A.Boguth,
and
J.J.Tesmer
(2010).
Structure and function of heterotrimeric G protein-regulated Rho guanine nucleotide exchange factors.
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Mol Pharmacol,
77,
111-125.
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R.D.Makde,
J.R.England,
H.P.Yennawar,
and
S.Tan
(2010).
Structure of RCC1 chromatin factor bound to the nucleosome core particle.
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Nature,
467,
562-566.
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PDB code:
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E.J.Friedman,
B.R.Temple,
S.N.Hicks,
J.Sondek,
C.D.Jones,
and
A.M.Jones
(2009).
Prediction of protein-protein interfaces on G-protein beta subunits reveals a novel phospholipase C beta2 binding domain.
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J Mol Biol,
392,
1044-1054.
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L.Guzman,
G.Moraga-Cid,
A.Avila,
M.Figueroa,
G.E.Yevenes,
J.Fuentealba,
and
L.G.Aguayo
(2009).
Blockade of ethanol-induced potentiation of glycine receptors by a peptide that interferes with Gbetagamma binding.
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J Pharmacol Exp Ther,
331,
933-939.
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M.S.Park,
A.L.Dessal,
A.V.Smrcka,
and
H.A.Stern
(2009).
Evaluating docking methods for prediction of binding affinities of small molecules to the G protein betagamma subunits.
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J Chem Inf Model,
49,
437-443.
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R.Prasobh,
and
N.Manoj
(2009).
The repertoire of heterotrimeric G proteins and RGS proteins in Ciona intestinalis.
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PLoS One,
4,
e7349.
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A.V.Smrcka
(2008).
G protein betagamma subunits: central mediators of G protein-coupled receptor signaling.
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Cell Mol Life Sci,
65,
2191-2214.
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A.V.Smrcka,
D.M.Lehmann,
and
A.L.Dessal
(2008).
G protein betagamma subunits as targets for small molecule therapeutic development.
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Comb Chem High Throughput Screen,
11,
382-395.
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C.A.Johnston,
A.J.Kimple,
P.M.Giguère,
and
D.P.Siderovski
(2008).
Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2.
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Structure,
16,
1086-1094.
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PDB code:
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C.A.Johnston,
F.S.Willard,
J.K.Ramer,
R.Blaesius,
C.N.Roques,
and
D.P.Siderovski
(2008).
State-selective binding peptides for heterotrimeric G-protein subunits: novel tools for investigating G-protein signaling dynamics.
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Comb Chem High Throughput Screen,
11,
370-381.
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D.H.Rosenzweig,
K.S.Nair,
J.Wei,
Q.Wang,
G.Garwin,
J.C.Saari,
C.K.Chen,
A.V.Smrcka,
A.Swaroop,
J.Lem,
J.B.Hurley,
and
V.Z.Slepak
(2007).
Subunit dissociation and diffusion determine the subcellular localization of rod and cone transducins.
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J Neurosci,
27,
5484-5494.
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J.B.Blumer,
A.V.Smrcka,
and
S.M.Lanier
(2007).
Mechanistic pathways and biological roles for receptor-independent activators of G-protein signaling.
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Pharmacol Ther,
113,
488-506.
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Y.Wu,
T.Buranda,
P.C.Simons,
G.P.Lopez,
W.E.McIntire,
J.C.Garrison,
E.R.Prossnitz,
and
L.A.Sklar
(2007).
Rapid-mix flow cytometry measurements of subsecond regulation of G protein-coupled receptor ternary complex dynamics by guanine nucleotides.
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Anal Biochem,
371,
10-20.
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C.A.Johnston,
E.S.Lobanova,
A.S.Shavkunov,
J.Low,
J.K.Ramer,
R.Blaesius,
Z.Fredericks,
F.S.Willard,
B.Kuhlman,
V.Y.Arshavsky,
and
D.P.Siderovski
(2006).
Minimal determinants for binding activated G alpha from the structure of a G alpha(i1)-peptide dimer.
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Biochemistry,
45,
11390-11400.
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PDB code:
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M.J.Cismowski
(2006).
Non-receptor activators of heterotrimeric G-protein signaling (AGS proteins).
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Semin Cell Dev Biol,
17,
334-344.
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T.M.Bonacci,
J.L.Mathews,
C.Yuan,
D.M.Lehmann,
S.Malik,
D.Wu,
J.L.Font,
J.M.Bidlack,
and
A.V.Smrcka
(2006).
Differential targeting of Gbetagamma-subunit signaling with small molecules.
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Science,
312,
443-446.
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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
