Peptide inhibitors of G protein-coupled receptor kinases
R. Winstel, H. Ihlenfeldt, G. Jung, C. Krasel, and M. Lohse. Biochem Pharmacol, 70 (7):
1001-8(October 2005)Winstel, Rainer Ihlenfeldt, Hans-Georg Jung, Gunther Krasel, Cornelius
Lohse, Martin J Research Support, Non-U.S. Gov't England Biochemical
pharmacology Biochem Pharmacol. 2005 Oct 1;70(7):1001-8..
Abstract
G protein-coupled receptor kinases (GRKs) are regulatory enzymes involved
in the modulation of seven-transmembrane-helix receptors. In order
to develop specific inhibitors for these kinases, we synthesized
and investigated peptide inhibitors derived from the sequence of
the first intracellular loop of the beta2-adrenergic receptor. Introduction
of changes in the sequence and truncation of N- and C-terminal amino
acids increased the inhibitory potency by a factor of 40. These inhibitors
not only inhibited the prototypical GRK2 but also GRK3 and GRK5.
In contrast there was no inhibition of protein kinase C and protein
kinase A even at the highest concentration tested. The peptide with
the sequence AKFERLQTVTNYFITSE inhibited GRK2 with an IC50 of 0.6
microM, GRK3 with 2.6 microM and GRK5 with 1.6 microM. The peptide
inhibitors were non-competitive for receptor and ATP. These findings
demonstrate that specific peptides can inhibit GRKs in the submicromolar
range and suggest that a further decrease in size is possible without
losing the inhibitory potency.
Winstel, Rainer Ihlenfeldt, Hans-Georg Jung, Gunther Krasel, Cornelius
Lohse, Martin J Research Support, Non-U.S. Gov't England Biochemical
pharmacology Biochem Pharmacol. 2005 Oct 1;70(7):1001-8.
%0 Journal Article
%1 Winstel2005
%A Winstel, R.
%A Ihlenfeldt, H. G.
%A Jung, G.
%A Krasel, C.
%A Lohse, M. J.
%D 2005
%J Biochem Pharmacol
%K & AMP/metabolism Acid Amino Cyclic Data Enzyme GTP-Binding Inhibitors/chemistry/*pharmacology Kinases/*antagonists Molecular Peptides/chemistry/*pharmacology Phosphorylation Protein-Tyrosine Receptor Sequence inhibitors/metabolism Proteins/metabolism
%N 7
%P 1001-8
%T Peptide inhibitors of G protein-coupled receptor kinases
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16102734
%V 70
%X G protein-coupled receptor kinases (GRKs) are regulatory enzymes involved
in the modulation of seven-transmembrane-helix receptors. In order
to develop specific inhibitors for these kinases, we synthesized
and investigated peptide inhibitors derived from the sequence of
the first intracellular loop of the beta2-adrenergic receptor. Introduction
of changes in the sequence and truncation of N- and C-terminal amino
acids increased the inhibitory potency by a factor of 40. These inhibitors
not only inhibited the prototypical GRK2 but also GRK3 and GRK5.
In contrast there was no inhibition of protein kinase C and protein
kinase A even at the highest concentration tested. The peptide with
the sequence AKFERLQTVTNYFITSE inhibited GRK2 with an IC50 of 0.6
microM, GRK3 with 2.6 microM and GRK5 with 1.6 microM. The peptide
inhibitors were non-competitive for receptor and ATP. These findings
demonstrate that specific peptides can inhibit GRKs in the submicromolar
range and suggest that a further decrease in size is possible without
losing the inhibitory potency.
@article{Winstel2005,
abstract = {G protein-coupled receptor kinases (GRKs) are regulatory enzymes involved
in the modulation of seven-transmembrane-helix receptors. In order
to develop specific inhibitors for these kinases, we synthesized
and investigated peptide inhibitors derived from the sequence of
the first intracellular loop of the beta2-adrenergic receptor. Introduction
of changes in the sequence and truncation of N- and C-terminal amino
acids increased the inhibitory potency by a factor of 40. These inhibitors
not only inhibited the prototypical GRK2 but also GRK3 and GRK5.
In contrast there was no inhibition of protein kinase C and protein
kinase A even at the highest concentration tested. The peptide with
the sequence AKFERLQTVTNYFITSE inhibited GRK2 with an IC50 of 0.6
microM, GRK3 with 2.6 microM and GRK5 with 1.6 microM. The peptide
inhibitors were non-competitive for receptor and ATP. These findings
demonstrate that specific peptides can inhibit GRKs in the submicromolar
range and suggest that a further decrease in size is possible without
losing the inhibitory potency.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Winstel, R. and Ihlenfeldt, H. G. and Jung, G. and Krasel, C. and Lohse, M. J.},
biburl = {https://www.bibsonomy.org/bibtex/2087b32c62055a31ff98f9bbfd63c308f/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {493f244d26e528ed0adfb92cd0de2279},
intrahash = {087b32c62055a31ff98f9bbfd63c308f},
issn = {0006-2952 (Print) 0006-2952 (Linking)},
journal = {Biochem Pharmacol},
keywords = {& AMP/metabolism Acid Amino Cyclic Data Enzyme GTP-Binding Inhibitors/chemistry/*pharmacology Kinases/*antagonists Molecular Peptides/chemistry/*pharmacology Phosphorylation Protein-Tyrosine Receptor Sequence inhibitors/metabolism Proteins/metabolism},
month = {Oct 1},
note = {Winstel, Rainer Ihlenfeldt, Hans-Georg Jung, Gunther Krasel, Cornelius
Lohse, Martin J Research Support, Non-U.S. Gov't England Biochemical
pharmacology Biochem Pharmacol. 2005 Oct 1;70(7):1001-8.},
number = 7,
pages = {1001-8},
shorttitle = {Peptide inhibitors of G protein-coupled receptor kinases},
timestamp = {2010-12-14T18:21:43.000+0100},
title = {Peptide inhibitors of G protein-coupled receptor kinases},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16102734},
volume = 70,
year = 2005
}