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.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Utepbergenov D,Derewenda U,Olekhnovich N,Szukalska G,Banerjee B,Hilinski MK,Lannigan DA,Stukenberg PT,Derewenda ZSdoi
10.1021/bi300620csubject
Has Abstractpub_date
2012-08-21 00:00:00pages
6499-510issue
33eissn
0006-2960issn
1520-4995journal_volume
51pub_type
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