The unusual mechanism of inhibition of the p90 ribosomal S6 kinase (RSK) by flavonol rhamnosides

Darkhan Utepbergenov, Zygmunt S. Derewenda

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 languageEnglish
Pages (from-to)1285-1291
Number of pages7
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1834
Issue number7
DOIs
Publication statusPublished - 2013
Externally publishedYes

Fingerprint

90-kDa Ribosomal Protein S6 Kinases
Phosphotransferases
Glycosides
Ribosomal Protein S6 Kinases
Rhamnose
Flavonols
Response Elements
Adenine
Protein Kinase Inhibitors
Metabolites
Scaffolds
Protein Kinases
Conformations
3-hydroxyflavone
Protein Isoforms
Nucleotides
Adenosine Triphosphate

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 journalArticle

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