3WE4
Crystal structure of S6K1 kinase domain in complex with a pyrimidine derivative PF-4708671 2-{[4-(5-ethylpyrimidin-4-yl)piperazin-1-yl]methyl}-5-(trifluoromethyl)-1H-benzimidazole
Summary for 3WE4
Entry DOI | 10.2210/pdb3we4/pdb |
Related | 3WF5 3WF6 3WF7 3WF8 3WF9 |
Descriptor | Ribosomal protein S6 kinase beta-1, ZINC ION, 2-{[4-(5-ethylpyrimidin-4-yl)piperazin-1-yl]methyl}-5-(trifluoromethyl)-1H-benzimidazole, ... (4 entities in total) |
Functional Keywords | serine/threonine protein kinase domain, transferase, phosphorylation, atp-binding, zinc-binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
Biological source | Homo sapiens (human) |
Cellular location | Cell junction, synapse, synaptosome . Isoform Alpha I: Nucleus. Isoform Alpha II: Cytoplasm: P23443 |
Total number of polymer chains | 1 |
Total formula weight | 37634.63 |
Authors | Niwa, H.,Shirouzu, M.,Yokoyama, S. (deposition date: 2013-06-29, release date: 2014-08-06, Last modification date: 2023-11-08) |
Primary citation | Niwa, H.,Mikuni, J.,Sasaki, S.,Tomabechi, Y.,Honda, K.,Ikeda, M.,Ohsawa, N.,Wakiyama, M.,Handa, N.,Shirouzu, M.,Honma, T.,Tanaka, A.,Yokoyama, S. Crystal structures of the S6K1 kinase domain in complexes with inhibitors J.Struct.Funct.Genom., 15:153-164, 2014 Cited by PubMed 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. PubMed: 25078151DOI: 10.1007/s10969-014-9188-8 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.995 Å) |
Structure validation
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