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Publication Abstract from PubMed

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-alpha-L-rhamnopyranoside), known as SL0101. Based on this structure, it was hypothesized that quercitrin (quercetin 3-O-alpha-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 microM as determined by isothermal titration calorimetry, and a crystal structure of the binary complex at 1.8 A 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+).

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 1.8 A resolution.,Derewenda U, Artamonov M, Szukalska G, Utepbergenov D, Olekhnovich N, Parikh HI, Kellogg GE, Somlyo AV, Derewenda ZS Acta Crystallogr D Biol Crystallogr. 2013 Feb;69(Pt 2):266-75. doi:, 10.1107/S0907444912045520. Epub 2013 Jan 19. PMID:23385462^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.