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.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
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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U2 - 10.1107/S0907444912045520
DO - 10.1107/S0907444912045520
M3 - Article
C2 - 23385462
AN - SCOPUS:84873607044
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 -