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 language | English |
|---|---|
| Pages (from-to) | 266-275 |
| Number of pages | 10 |
| Journal | Acta Crystallographica Section D: Biological Crystallography |
| Volume | 69 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2013 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Identification of quercitrin as an inhibitor of the p90 S6 ribosomal kinase (RSK)
T2 - Structure of its complex with the N-terminal domain of RSK2 at 1.8Å resolution
AU - Derewenda, Urszula
AU - Artamonov, Mykhaylo
AU - Szukalska, Gabriela
AU - Utepbergenov, Darkhan
AU - Olekhnovich, Natalya
AU - Parikh, Hardik I.
AU - Kellogg, Glen E.
AU - Somlyo, Avril V.
AU - Derewenda, Zygmunt S.
PY - 2013/2
Y1 - 2013/2
N2 - 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+.
AB - 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+.
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UR - http://www.scopus.com/inward/citedby.url?scp=84873607044&partnerID=8YFLogxK
U2 - 10.1107/S0907444912045520
DO - 10.1107/S0907444912045520
M3 - Article
VL - 69
SP - 266
EP - 275
JO - Acta Crystallographica Section D: Structural Biology
JF - Acta Crystallographica Section D: Structural Biology
SN - 0907-4449
IS - 2
ER -