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Title: 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

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-a-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 {angstrom} 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 aD-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.

Authors:
; ; ; ; ; ; ; ;  [1]
  1. Lodz - Poland
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
UNIVERSITYNIH
OSTI Identifier:
1050756
Resource Type:
Journal Article
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 51; Journal Issue: 33
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ATOMIC MODELS; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DRUGS; GLYCOSIDES; INHIBITION; NEOPLASMS; NUCLEOTIDES; OPTIMIZATION; PHOSPHOTRANSFERASES; POTENTIALS; PROTEINS; RESOLUTION; TARGETS

Citation Formats

Utepbergenov, Darkhan, Derewenda, Urszula, Olekhnovich, Natalya, Szukalska, Gabriela, Banerjee, Budhaditya, Hilinski, Michael K, Lannigan, Deborah A, Stukenberg, P Todd, Derewenda, Zygmunt S, and UV). 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. United States: N. p., 2012. Web. doi:10.1021/bi300620c.
Utepbergenov, Darkhan, Derewenda, Urszula, Olekhnovich, Natalya, Szukalska, Gabriela, Banerjee, Budhaditya, Hilinski, Michael K, Lannigan, Deborah A, Stukenberg, P Todd, Derewenda, Zygmunt S, & UV). 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. United States. https://doi.org/10.1021/bi300620c
Utepbergenov, Darkhan, Derewenda, Urszula, Olekhnovich, Natalya, Szukalska, Gabriela, Banerjee, Budhaditya, Hilinski, Michael K, Lannigan, Deborah A, Stukenberg, P Todd, Derewenda, Zygmunt S, and UV). 2012. "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". United States. https://doi.org/10.1021/bi300620c.
@article{osti_1050756,
title = {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},
author = {Utepbergenov, Darkhan and Derewenda, Urszula and Olekhnovich, Natalya and Szukalska, Gabriela and Banerjee, Budhaditya and Hilinski, Michael K and Lannigan, Deborah A and Stukenberg, P Todd and Derewenda, Zygmunt S and UV)},
abstractNote = {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-a-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 {angstrom} 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 aD-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.},
doi = {10.1021/bi300620c},
url = {https://www.osti.gov/biblio/1050756}, journal = {Biochemistry},
number = 33,
volume = 51,
place = {United States},
year = {Tue Sep 11 00:00:00 EDT 2012},
month = {Tue Sep 11 00:00:00 EDT 2012}
}