Open AccessIdentification of quercitrin as an inhibitor of the p90 S6 ribosomal kinase (RSK): structure of its complex with the N‐terminal domain of RSK2 at 1.8 Å resolution
Author(s) -
Derewenda Urszula,
Artamonov Mykhaylo,
Szukalska Gabriela,
Utepbergenov Darkhan,
Olekhnovich Natalya,
Parikh Hardik I.,
Kellogg Glen E.,
Somlyo Avril V.,
Derewenda Zygmunt S.
Publication year - 2013
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s0907444912045520
Subject(s) - quercitrin , chemistry , isothermal titration calorimetry , quercetin , stereochemistry , dissociation constant , kaempferol , kinase , biochemistry , crystallography , biophysics , biology , receptor , antioxidant
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‐α‐L‐rhamnopyranoside), known as SL0101. Based on this structure, it was hypothesized that quercitrin (quercetin 3‐ O ‐α‐L‐rhamnopyranoside), a related but ubiquitous and inexpensive compound, might also act as an RSK inhibitor. Here, it is demonstrated that quercitrin binds to RSK2 NTKD with a dissociation constant ( K d ) of 5.8 µ M as determined by isothermal titration calorimetry, and a crystal structure of the binary complex at 1.8 Å 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 Ca 2+ .