title: 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 Å resolution.
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-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 µM 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+).
authors: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA.
authors: Urszula
authors: U
authors: Derewenda
authors: Mykhaylo
authors: M
authors: Artamonov
authors: Gabriela
authors: G
authors: Szukalska
authors: Darkhan
authors: D
authors: Utepbergenov
authors: Natalya
authors: N
authors: Olekhnovich
authors: Hardik I
authors: HI
authors: Parikh
authors: Glen E
authors: GE
authors: Kellogg
authors: Avril V
authors: AV
authors: Somlyo
authors: Zygmunt S
authors: ZS
authors: Derewenda
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D051379:Mice; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011794:Quercetin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C012526:quercitrin; D011794:Quercetin; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3
keywords: SL0101; flavonol glycosides; inhibitors; protein kinases; quercitrin
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