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PDBsum entry 2ode
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Signaling protein
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PDB id
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2ode
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Contents |
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316 a.a.
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131 a.a.
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116 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural diversity in the rgs domain and its interaction with heterotrimeric g protein alpha-Subunits.
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Authors
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M.Soundararajan,
F.S.Willard,
A.J.Kimple,
A.P.Turnbull,
L.J.Ball,
G.A.Schoch,
C.Gileadi,
O.Y.Fedorov,
E.F.Dowler,
V.A.Higman,
S.Q.Hutsell,
M.Sundström,
D.A.Doyle,
D.P.Siderovski.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
6457-6462.
[DOI no: ]
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PubMed id
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Abstract
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Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by
Galpha subunits and thus facilitate termination of signaling initiated by G
protein-coupled receptors (GPCRs). RGS proteins hold great promise as disease
intervention points, given their signature role as negative regulators of
GPCRs-receptors to which the largest fraction of approved medications are
currently directed. RGS proteins share a hallmark RGS domain that interacts most
avidly with Galpha when in its transition state for GTP hydrolysis; by binding
and stabilizing switch regions I and II of Galpha, RGS domain binding
consequently accelerates Galpha-mediated GTP hydrolysis. The human genome
encodes more than three dozen RGS domain-containing proteins with varied Galpha
substrate specificities. To facilitate their exploitation as drug-discovery
targets, we have taken a systematic structural biology approach toward
cataloging the structural diversity present among RGS domains and identifying
molecular determinants of their differential Galpha selectivities. Here, we
determined 14 structures derived from NMR and x-ray crystallography of members
of the R4, R7, R12, and RZ subfamilies of RGS proteins, including 10 uncomplexed
RGS domains and 4 RGS domain/Galpha complexes. Heterogeneity observed in the
structural architecture of the RGS domain, as well as in engagement of switch
III and the all-helical domain of the Galpha substrate, suggests that unique
structural determinants specific to particular RGS protein/Galpha pairings exist
and could be used to achieve selective inhibition by small molecules.
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Figure 1.
Heterogeneity in the αV–αVII regions of R12 subfamily RGS
domains versus the canonical RGS domain fold of R4, R7, and RZ
subfamily members. (A) Apo-RGS domains of R4 subfamily member
RGS8 (green; PDB ID 2IHD), R7 subfamily member RGS9 (orange; PDB
ID 1FQI), and RZ subfamily member RGS19 (gray; PDB ID 1CMZ) were
aligned along helices αIV and αV and superimposed by using
PyMOL. (B–D) Apo-RGS domains of RGS14 (B) (blue; PDB ID 2JNU),
RGS10 from this study (C) (salmon; PDB ID 2I59), and RGS10 from
Yokoyama et al. (D) (light purple; PDB ID 2DLR) are presented to
highlight differences in the αV–αVI–αVII region. The
heterogeneous αVI regions are specifically highlighted in cyan
(B), red (C), and magenta (D), respectively.
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Figure 2.
Predicted structural determinants of Gα selectivity by RGS2.
(A) RGS1 (gray-blue) bound to Gα[i1] (α1 helix in light red;
switch I in orange) is presented to highlight the Gα switch-I
interaction interface (PDB ID 2GTP). Asp-172 of RGS1 is within
hydrogen-bonding distance of the backbone amine of Thr-182 in
Gα[i1] and additionally stabilized by the terminal amines of
the highly conserved Arg-176 in the RGS1 αVII helix. Ser-95 is
placed within close proximity (≤4.0 Å) of three Gα[i1]
residues (Thr-182, Gly-183, and Lys-210). (B) Residues 170–190
of RGS2 (PDB ID 2AF0) were superimposed on residues 159–179 of
RGS1 from the RGS1/Gα[i1] complex (PDB ID 2GTP) with an
r.m.s.d. of 0.5 Å. RGS1 is not shown, RGS2 is presented in
green, and Gα[i1] is rendered in light red (α1 helix) and
orange (switch I). Asparagine at position 184 in RGS2 (normally
an aspartate in R4 subfamily members) does not allow for the
hydrogen bond to the peptide bond amine of Thr-182 in Gα[i1];
however, Asn-184 can potentially form a hydrogen bond with the
backbone carbonyl of Lys-180. The increased atomic radius of
Cys-106 in RGS2 (versus serine in RGS1) may cause steric
hindrance with the switch-I backbone and the side-chain of
Lys-210.
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