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PDBsum entry 4yhj
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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 and function of the hypertension variant a486v of g protein-Coupled receptor kinase 4.
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Authors
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S.J.Allen,
G.Parthasarathy,
P.L.Darke,
R.E.Diehl,
R.E.Ford,
D.L.Hall,
S.A.Johnson,
J.C.Reid,
K.W.Rickert,
J.M.Shipman,
S.M.Soisson,
P.Zuck,
S.K.Munshi,
K.J.Lumb.
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Ref.
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J Biol Chem, 2015,
290,
20360-20373.
[DOI no: ]
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PubMed id
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Abstract
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G-protein-coupled receptor (GPCR) kinases (GRKs) bind to and phosphorylate
GPCRs, initiating the process of GPCR desensitization and internalization. GRK4
is implicated in the regulation of blood pressure, and three GRK4 polymorphisms
(R65L, A142V, and A486V) are associated with hypertension. Here, we describe the
2.6 Å structure of human GRK4α A486V crystallized in the presence of
5'-adenylyl β,γ-imidodiphosphate. The structure of GRK4α is similar to other
GRKs, although slight differences exist within the RGS homology (RH) bundle
subdomain, substrate-binding site, and kinase C-tail. The RH bundle subdomain
and kinase C-terminal lobe form a strikingly acidic surface, whereas the kinase
N-terminal lobe and RH terminal subdomain surfaces are much more basic. In this
respect, GRK4α is more similar to GRK2 than GRK6. A fully ordered kinase C-tail
reveals interactions linking the C-tail with important determinants of kinase
activity, including the αB helix, αD helix, and the P-loop.
Autophosphorylation of wild-type GRK4α is required for full kinase activity, as
indicated by a lag in phosphorylation of a peptide from the dopamine D1 receptor
without ATP preincubation. In contrast, this lag is not observed in GRK4α
A486V. Phosphopeptide mapping by mass spectrometry indicates an increased rate
of autophosphorylation of a number of residues in GRK4α A486V relative to
wild-type GRK4α, including Ser-485 in the kinase C-tail.
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