title: Crystal structures of the S6K1 kinase domain in complexes with inhibitors.
abstract: Ribosomal protein S6 kinase 1 (S6K1) is a serine/threonine protein kinase that plays an important role in the PIK3/mTOR signaling pathway, and is implicated in diseases including diabetes, obesity, and cancer. The crystal structures of the S6K1 kinase domain in complexes with staurosporine and the S6K1-specific inhibitor PF-4708671 have been reported. In the present study, five compounds (F108, F109, F176, F177, and F179) were newly identified by in silico screening of a chemical library and kinase assay. The crystal structures of the five inhibitors in complexes with the S6K1 kinase domain were determined at resolutions between 1.85 and 2.10 Å. All of the inhibitors bound to the ATP binding site, lying along the P-loop, while the activation loop stayed in the inactive form. Compound F179, with a carbonyl group in the middle of the molecule, altered the αC helix conformation by interacting with the invariant Lys123. Compounds F176 and F177 bound slightly distant from the hinge region, and their sulfoamide groups formed polar interactions with the protein. The structural features required for the specific binding of inhibitors are discussed.
authors: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, 230-0045, Japan.
authors: Hideaki
authors: H
authors: Niwa
authors: Junko
authors: J
authors: Mikuni
authors: Shunta
authors: S
authors: Sasaki
authors: Yuri
authors: Y
authors: Tomabechi
authors: Keiko
authors: K
authors: Honda
authors: Mariko
authors: M
authors: Ikeda
authors: Noboru
authors: N
authors: Ohsawa
authors: Motoaki
authors: M
authors: Wakiyama
authors: Noriko
authors: N
authors: Handa
authors: Mikako
authors: M
authors: Shirouzu
authors: Teruki
authors: T
authors: Honma
authors: Akiko
authors: A
authors: Tanaka
authors: Shigeyuki
authors: S
authors: Yokoyama
mesh_terms: D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000648:ultrastructure*; D019311:Staurosporine / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; C552719:PF-4708671; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D019311:Staurosporine