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PDBsum entry 4jqi
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Signaling protein
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PDB id
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4jqi
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Contents |
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353 a.a.
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204 a.a.
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185 a.a.
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21 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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Structure of active β-Arrestin-1 bound to a g-Protein-Coupled receptor phosphopeptide.
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Authors
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A.K.Shukla,
A.Manglik,
A.C.Kruse,
K.Xiao,
R.I.Reis,
W.C.Tseng,
D.P.Staus,
D.Hilger,
S.Uysal,
L.Y.Huang,
M.Paduch,
P.Tripathi-Shukla,
A.Koide,
S.Koide,
W.I.Weis,
A.A.Kossiakoff,
B.K.Kobilka,
R.J.Lefkowitz.
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Ref.
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Nature, 2013,
497,
137-141.
[DOI no: ]
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PubMed id
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Abstract
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The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and
modulated by three families of proteins: the heterotrimeric G proteins, the
G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate
activation of second-messenger-generating enzymes and other effectors, GRKs
phosphorylate activated receptors, and arrestins subsequently bind
phosphorylated receptors and cause receptor desensitization. Arrestins activated
by interaction with phosphorylated receptors can also mediate
G-protein-independent signalling by serving as adaptors to link receptors to
numerous signalling pathways. Despite their central role in regulation and
signalling of GPCRs, a structural understanding of β-arrestin activation and
interaction with GPCRs is still lacking. Here we report the crystal structure of
β-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated
29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin
receptor (V2Rpp). This peptide has previously been shown to functionally and
conformationally activate β-arrestin-1 (ref. 5). To capture this active
conformation, we used a conformationally selective synthetic antibody fragment
(Fab30) that recognizes the phosphopeptide-activated state of β-arrestin-1. The
structure of the β-arrestin-1-V2Rpp-Fab30 complex shows marked conformational
differences in β-arrestin-1 compared to its inactive conformation. These
include rotation of the amino- and carboxy-terminal domains relative to each
other, and a major reorientation of the 'lariat loop' implicated in maintaining
the inactive state of β-arrestin-1. These results reveal, at high resolution, a
receptor-interacting interface on β-arrestin, and they indicate a potentially
general molecular mechanism for activation of these multifunctional signalling
and regulatory proteins.
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