Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 Å crystal structure of the N-terminal domain of RSK2 with bound inhibitor

Darkhan Utepbergenov, Urszula Derewenda, Natalya Olekhnovich, Gabriela Szukalska, Budhaditya Banerjee, Michael K. Hilinski, Deborah A. Lannigan, P. Todd Stukenberg, Zygmunt S. Derewenda

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The p90 ribosomal S6 family of kinases (RSK) are potential drug targets, due to their involvement in cancer and other pathologies. There are currently only two known selective inhibitors of RSK, but the basis for selectivity is not known. One of these inhibitors is a naturally occurring kaempferol-α-l- diacetylrhamnoside, SL0101. Here, we report the crystal structure of the complex of the N-terminal kinase domain of the RSK2 isoform with SL0101 at 1.5 Å resolution. The refined atomic model reveals unprecedented structural reorganization of the protein moiety, as compared to the nucleotide-bound form. The entire N-lobe, the hinge region, and the αD-helix undergo dramatic conformational changes resulting in a rearrangement of the nucleotide binding site with concomitant formation of a highly hydrophobic pocket spatially suited to accommodate SL0101. These unexpected results will be invaluable in further optimization of the SL0101 scaffold as a promising lead for a novel class of kinase inhibitors.

Original languageEnglish
Pages (from-to)6499-6510
Number of pages12
JournalBiochemistry
Volume51
Issue number33
DOIs
Publication statusPublished - Aug 21 2012
Externally publishedYes

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90-kDa Ribosomal Protein S6 Kinases
Glycosides
Crystal structure
Phosphotransferases
Nucleotides
Ribosomal Protein S6 Kinases
Pathology
Hinges
Scaffolds
Protein Isoforms
Binding Sites
SL0101
3-hydroxyflavone
Pharmaceutical Preparations
Neoplasms
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 Å crystal structure of the N-terminal domain of RSK2 with bound inhibitor. / Utepbergenov, Darkhan; Derewenda, Urszula; Olekhnovich, Natalya; Szukalska, Gabriela; Banerjee, Budhaditya; Hilinski, Michael K.; Lannigan, Deborah A.; Stukenberg, P. Todd; Derewenda, Zygmunt S.

In: Biochemistry, Vol. 51, No. 33, 21.08.2012, p. 6499-6510.

Research output: Contribution to journalArticle

Utepbergenov, Darkhan ; Derewenda, Urszula ; Olekhnovich, Natalya ; Szukalska, Gabriela ; Banerjee, Budhaditya ; Hilinski, Michael K. ; Lannigan, Deborah A. ; Stukenberg, P. Todd ; Derewenda, Zygmunt S. / Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 Å crystal structure of the N-terminal domain of RSK2 with bound inhibitor. In: Biochemistry. 2012 ; Vol. 51, No. 33. pp. 6499-6510.
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