title: Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors.
abstract: 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 A resolution. The activation loop and helix alphaC, key regulatory elements of kinase function, are disordered. The DFG motif of the inactive RSK1 adopts an "active-like" conformation. The beta-PO(4) 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.
authors.affiliation: Department of Structural Biology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. mari_ikuta@.merck.com
authors.forename: Mari
authors.initials: M
authors.lastname: Ikuta
authors.forename: Maria
authors.initials: M
authors.lastname: Kornienko
authors.forename: Noel
authors.initials: N
authors.lastname: Byrne
authors.forename: John C
authors.initials: JC
authors.lastname: Reid
authors.forename: Shinji
authors.initials: S
authors.lastname: Mizuarai
authors.forename: Hidehito
authors.initials: H
authors.lastname: Kotani
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D020816:Amino Acid Motifs; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011687:Purines / Q000737:chemistry* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000737:chemistry* / Q000378:metabolism; D019311:Staurosporine / Q000737:chemistry* / Q000378:metabolism
chemical_list: C471843:6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine; D008024:Ligands; D011687:Purines; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; D000255:Adenosine Triphosphate; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D019311:Staurosporine