Identification of quercitrin as an inhibitor of the p90 S6 ribosomal kinase (RSK): Structure of its complex with the N-terminal domain of RSK2 at 1.8Å resolution

Urszula Derewenda, Mykhaylo Artamonov, Gabriela Szukalska, Darkhan Utepbergenov, Natalya Olekhnovich, Hardik I. Parikh, Glen E. Kellogg, Avril V. Somlyo, Zygmunt S. Derewenda

Research output: Contribution to journalArticle

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Abstract

Members of the RSK family of kinases constitute attractive targets for drug design, but a lack of structural information regarding the mechanism of selective inhibitors impedes progress in this field. The crystal structure of the N-terminal kinase domain (residues 45-346) of mouse RSK2, or RSK2 NTKD, has recently been described in complex with one of only two known selective inhibitors, a rare naturally occurring flavonol glycoside, kaempferol 3-O-(3′′,4′′-di-O-acetyl-l-rhamnopyranoside), known as SL0101. Based on this structure, it was hypothesized that quercitrin (quercetin 3-O-l-rhamnopyranoside), a related but ubiquitous and inexpensive compound, might also act as an RSK inhibitor. Here, it is demonstrated that quercitrin binds to RSK2NTKD with a dissociation constant (K d) of 5.8μM as determined by isothermal titration calorimetry, and a crystal structure of the binary complex at 1.8Å resolution is reported. The crystal structure reveals a very similar mode of binding to that recently reported for SL0101. Closer inspection shows a number of small but significant differences that explain the slightly higher K d for quercitrin compared with SL0101. It is also shown that quercitrin can effectively substitute for SL0101 in a biological assay, in which it significantly suppresses the contractile force in rabbit pulmonary artery smooth muscle in response to Ca2+.

Original languageEnglish
Pages (from-to)266-275
Number of pages10
JournalActa Crystallographica Section D: Biological Crystallography
Volume69
Issue number2
DOIs
Publication statusPublished - Feb 2013
Externally publishedYes

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90-kDa Ribosomal Protein S6 Kinases
Phosphotransferases
Calorimetry
Drug Design
Quercetin
Glycosides
Biological Assay
Pulmonary Artery
Smooth Muscle
Rabbits
SL0101
quercitrin

ASJC Scopus subject areas

  • Structural Biology

Cite this

Identification of quercitrin as an inhibitor of the p90 S6 ribosomal kinase (RSK) : Structure of its complex with the N-terminal domain of RSK2 at 1.8Å resolution. / Derewenda, Urszula; Artamonov, Mykhaylo; Szukalska, Gabriela; Utepbergenov, Darkhan; Olekhnovich, Natalya; Parikh, Hardik I.; Kellogg, Glen E.; Somlyo, Avril V.; Derewenda, Zygmunt S.

In: Acta Crystallographica Section D: Biological Crystallography, Vol. 69, No. 2, 02.2013, p. 266-275.

Research output: Contribution to journalArticle

Derewenda, Urszula ; Artamonov, Mykhaylo ; Szukalska, Gabriela ; Utepbergenov, Darkhan ; Olekhnovich, Natalya ; Parikh, Hardik I. ; Kellogg, Glen E. ; Somlyo, Avril V. ; Derewenda, Zygmunt S. / Identification of quercitrin as an inhibitor of the p90 S6 ribosomal kinase (RSK) : Structure of its complex with the N-terminal domain of RSK2 at 1.8Å resolution. In: Acta Crystallographica Section D: Biological Crystallography. 2013 ; Vol. 69, No. 2. pp. 266-275.
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