Abstract
All known protein kinases share a bilobal kinase domain with well conserved structural elements. Because of significant structural similarities of nucleotide binding pocket, the development of highly selective kinase inhibitors is a very challenging task. Flavonols, naturally occurring plant metabolites, have long been known to inhibit kinases by mimicking the adenine moiety. Interestingly, recent data show that some flavonol glycosides are more selective, although underlying mechanisms were unknown. Crystallographic data from our laboratory revealed that the N-terminal kinase domain of p90 ribosomal S6 kinase, isoform 2, binds three different flavonol rhamnosides in a highly unusual manner, distinct from other kinase inhibitor interactions. The kinase domain undergoes a reorganization of several structural elements in response to the binding of the inhibitors. Specifically, the main β-sheet of the N-lobe undergoes a twisting rotation by ~ 56 around an axis passing through the N- and C-lobes, leading to the restructuring of the canonical ATP-binding pocket into pockets sterically adapted to the inhibitor shape. The flavonol rhamnosides appear to adopt compact, but strained conformations with the rhamnose moiety swept under the B-ring of flavonol, unlike the structure of the free counterparts in solution. These data suggest that the flavonol glycoside scaffold could be used as a template for new inhibitors selective for the RSK family. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
| Original language | English |
|---|---|
| Pages (from-to) | 1285-1291 |
| Number of pages | 7 |
| Journal | Biochimica et Biophysica Acta - Proteins and Proteomics |
| Volume | 1834 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2013 |
| Externally published | Yes |
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Keywords
- Conformational selection
- Flavonol
- Induced fit
- Quercitrin
- RSK kinase
- SL0101
ASJC Scopus subject areas
- Biochemistry
- Biophysics
- Analytical Chemistry
- Molecular Biology
Cite this
The unusual mechanism of inhibition of the p90 ribosomal S6 kinase (RSK) by flavonol rhamnosides. / Utepbergenov, Darkhan; Derewenda, Zygmunt S.
In: Biochimica et Biophysica Acta - Proteins and Proteomics, Vol. 1834, No. 7, 2013, p. 1285-1291.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The unusual mechanism of inhibition of the p90 ribosomal S6 kinase (RSK) by flavonol rhamnosides
AU - Utepbergenov, Darkhan
AU - Derewenda, Zygmunt S.
PY - 2013
Y1 - 2013
N2 - All known protein kinases share a bilobal kinase domain with well conserved structural elements. Because of significant structural similarities of nucleotide binding pocket, the development of highly selective kinase inhibitors is a very challenging task. Flavonols, naturally occurring plant metabolites, have long been known to inhibit kinases by mimicking the adenine moiety. Interestingly, recent data show that some flavonol glycosides are more selective, although underlying mechanisms were unknown. Crystallographic data from our laboratory revealed that the N-terminal kinase domain of p90 ribosomal S6 kinase, isoform 2, binds three different flavonol rhamnosides in a highly unusual manner, distinct from other kinase inhibitor interactions. The kinase domain undergoes a reorganization of several structural elements in response to the binding of the inhibitors. Specifically, the main β-sheet of the N-lobe undergoes a twisting rotation by ~ 56 around an axis passing through the N- and C-lobes, leading to the restructuring of the canonical ATP-binding pocket into pockets sterically adapted to the inhibitor shape. The flavonol rhamnosides appear to adopt compact, but strained conformations with the rhamnose moiety swept under the B-ring of flavonol, unlike the structure of the free counterparts in solution. These data suggest that the flavonol glycoside scaffold could be used as a template for new inhibitors selective for the RSK family. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
AB - All known protein kinases share a bilobal kinase domain with well conserved structural elements. Because of significant structural similarities of nucleotide binding pocket, the development of highly selective kinase inhibitors is a very challenging task. Flavonols, naturally occurring plant metabolites, have long been known to inhibit kinases by mimicking the adenine moiety. Interestingly, recent data show that some flavonol glycosides are more selective, although underlying mechanisms were unknown. Crystallographic data from our laboratory revealed that the N-terminal kinase domain of p90 ribosomal S6 kinase, isoform 2, binds three different flavonol rhamnosides in a highly unusual manner, distinct from other kinase inhibitor interactions. The kinase domain undergoes a reorganization of several structural elements in response to the binding of the inhibitors. Specifically, the main β-sheet of the N-lobe undergoes a twisting rotation by ~ 56 around an axis passing through the N- and C-lobes, leading to the restructuring of the canonical ATP-binding pocket into pockets sterically adapted to the inhibitor shape. The flavonol rhamnosides appear to adopt compact, but strained conformations with the rhamnose moiety swept under the B-ring of flavonol, unlike the structure of the free counterparts in solution. These data suggest that the flavonol glycoside scaffold could be used as a template for new inhibitors selective for the RSK family. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
KW - Conformational selection
KW - Flavonol
KW - Induced fit
KW - Quercitrin
KW - RSK kinase
KW - SL0101
UR - http://www.scopus.com/inward/record.url?scp=84878884719&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878884719&partnerID=8YFLogxK
U2 - 10.1016/j.bbapap.2013.03.018
DO - 10.1016/j.bbapap.2013.03.018
M3 - Article
C2 - 23541530
AN - SCOPUS:84878884719
VL - 1834
SP - 1285
EP - 1291
JO - Biochimica et Biophysica Acta - Proteins and Proteomics
JF - Biochimica et Biophysica Acta - Proteins and Proteomics
SN - 1570-9639
IS - 7
ER -