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Crystal structures of the S6K1 kinase domain in complexes with inhibitors.

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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
OpenAccess logo J Struct Funct Genomics 15 153-64 (2014)
Related entries: 3we4, 3wf5, 3wf6, 3wf7, 3wf8

Cited: 6 times
EuropePMC logo PMID: 25078151

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.

Articles - 3wf9 mentioned but not cited (1)

  1. Crystal structures of the S6K1 kinase domain in complexes with inhibitors. 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. J. Struct. Funct. Genomics 15 153-164 (2014)


Reviews citing this publication (1)

  1. Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network. D'Incal C, Broos J, Torfs T, Kooy RF, Vanden Berghe W. Cells 11 1325 (2022)

Articles citing this publication (4)

  1. Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice. Bhattacharya A, Mamcarz M, Mullins C, Choudhury A, Boyle RG, Smith DG, Walker DW, Klann E. Neuropsychopharmacology 41 1991-2000 (2016)
  2. Discovery of a Potent and Highly Isoform-Selective Inhibitor of the Neglected Ribosomal Protein S6 Kinase Beta 2 (S6K2). Gerstenecker S, Haarer L, Schröder M, Kudolo M, Schwalm MP, Wydra V, Serafim RAM, Chaikuad A, Knapp S, Laufer S, Gehringer M. Cancers (Basel) 13 5133 (2021)
  3. Discovery of novel S6K1 inhibitors by an ensemble-based virtual screening method and molecular dynamics simulation. Zhang H, Zhang HR, Zhang J, Hu ML, Ren L, Luo QQ, Qi HZ. J Mol Model 29 102 (2023)
  4. Identification of a novel S6K1 inhibitor, rosmarinic acid methyl ester, for treating cisplatin-resistant cervical cancer. Nam KH, Yi SA, Nam G, Noh JS, Park JW, Lee MG, Park JH, Oh H, Lee J, Lee KR, Park HJ, Lee J, Han JW. BMC Cancer 19 773 (2019)


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