4GUE

Structure of N-terminal kinase domain of RSK2 with flavonoid glycoside quercitrin

Summary for 4GUE

• Entry DOI: 10.2210/pdb4gue/pdb
• Related: 3UBD 4EL9
• Descriptor: Ribosomal protein S6 kinase alpha-3, 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-oxo-4H-chromen-3-yl 6-deoxy-alpha-L-mannopyranoside, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: serine/threonine kinase domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mus musculus (mouse)
• Cellular location: Nucleus (By similarity): P18654
• Total number of polymer chains: 1
• Total formula weight: 35639.58

Authors

Derewenda, U.,Utepbergenov, D.,Szukalska, G.,Derewenda, Z.S. (deposition date: 2012-08-29, release date: 2013-01-30, Last modification date: 2023-09-13)

Primary citation

Derewenda, U.,Artamonov, M.,Szukalska, G.,Utepbergenov, D.,Olekhnovich, N.,Parikh, H.I.,Kellogg, G.E.,Somlyo, A.V.,Derewenda, Z.S.
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.
Acta Crystallogr.,Sect.D, 69:266-275, 2013

PubMed 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+).

PubMed: 23385462
DOI: 10.1107/S0907444912045520

Experimental method

X-RAY DIFFRACTION (1.8 Å)