3UBD

Structure of N-terminal domain of RSK2 kinase in complex with flavonoid glycoside SL0101

Summary for 3UBD

• Entry DOI: 10.2210/pdb3ubd/pdb
• Descriptor: Ribosomal protein S6 kinase alpha-3, 5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl 3,4-di-O-acetyl-6-deoxy-alpha-L-mannopyranoside (3 entities in total)
• Functional Keywords: kinase-inhibitor complex, induced fit, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mus musculus (mouse)
• Cellular location: Nucleus : P18654
• Total number of polymer chains: 1
• Total formula weight: 35516.21

Authors

Utepbergenov, D.,Derewenda, U.,Derewenda, Z.S. (deposition date: 2011-10-24, release date: 2012-09-05, Last modification date: 2023-09-13)

Primary citation

Utepbergenov, D.,Derewenda, U.,Olekhnovich, N.,Szukalska, G.,Banerjee, B.,Hilinski, M.K.,Lannigan, D.A.,Stukenberg, P.T.,Derewenda, Z.S.
Insights into the Inhibition of the p90 Ribosomal S6 Kinase (RSK) by the Flavonol Glycoside SL0101 from the 1.5 A Crystal Structure of the N-Terminal Domain of RSK2 with Bound Inhibitor.
Biochemistry, 51:6499-6510, 2012

PubMed Abstract: The p90 ribosomal S6 family of kinases (RSK) are potential drug targets, due to their involvement in cancer and other pathologies. There are currently only two known selective inhibitors of RSK, but the basis for selectivity is not known. One of these inhibitors is a naturally occurring kaempferol-α-L-diacetylrhamnoside, SL0101. Here, we report the crystal structure of the complex of the N-terminal kinase domain of the RSK2 isoform with SL0101 at 1.5 Å resolution. The refined atomic model reveals unprecedented structural reorganization of the protein moiety, as compared to the nucleotide-bound form. The entire N-lobe, the hinge region, and the αD-helix undergo dramatic conformational changes resulting in a rearrangement of the nucleotide binding site with concomitant formation of a highly hydrophobic pocket spatially suited to accommodate SL0101. These unexpected results will be invaluable in further optimization of the SL0101 scaffold as a promising lead for a novel class of kinase inhibitors.

PubMed: 22846040
DOI: 10.1021/bi300620c

Experimental method

X-RAY DIFFRACTION (1.53 Å)