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Published online before print October 26, 2007, 10.1110/ps.073123707
Protein Science (2007), 16:2626-2635. Published by Cold Spring Harbor Laboratory Press. Copyright © 2007 The Protein Society
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Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors

Mari Ikuta1, Maria Kornienko1, Noel Byrne1, John C. Reid1, Shinji Mizuarai2, Hidehito Kotani2, and Sanjeev K. Munshi1

1 Department of Structural Biology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
2 Department of Cancer Research, Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Tsukuba, Ibaraki 300-2611, Japan

(RECEIVED July 15, 2007; FINAL REVISION September 10, 2007; ACCEPTED September 12, 2007)

The p90 ribosomal S6 kinases (RSKs) also known as MAPKAP-Ks are serine/threonine protein kinases that are activated by ERK or PDK1 and act as downstream effectors of mitogen-activated protein kinase (MAPK). RSK1, a member of the RSK family, contains two distinct kinase domains in a single polypeptide chain, the regulatory C-terminal kinase domain (CTKD) and the catalytic N-terminal kinase domain (NTKD). Autophosphorylation of the CTKD leads to activation of the NTKD that subsequently phosphorylates downstream substrates. Here we report the crystal structures of the unactivated RSK1 NTKD bound to different ligands at 2.0 Å resolution. The activation loop and helix {alpha}C, key regulatory elements of kinase function, are disordered. The DFG motif of the inactive RSK1 adopts an "active-like" conformation. The beta-PO4 group in the AMP–PCP complex adopts a unique conformation that may contribute to inactivity of the enzyme. Structures of RSK1 ligand complexes offer insights into the design of novel anticancer agents and into the regulation of the catalytic activity of RSKs.

Keywords: RSK1; kinase; cancer; crystal structure; kinase inhibitor


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