4RLP

Human p70s6k1 with ruthenium-based inhibitor FL772

4RLP の概要

• エントリーDOI: 10.2210/pdb4rlp/pdb
• 関連するPDBエントリー: 4RLO
• 分子名称: p70S6K1, [(amino-kappaN)methanethiolato](3-fluoro-9-methoxypyrido[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dionato-kappa~2~N,N')(N-methyl-1,4,7-trithiecan-9-amine-kappa~3~S~1~,S~4~,S~7~)ruthenium, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell junction, synapse, synaptosome . Isoform Alpha I: Nucleus. Isoform Alpha II: Cytoplasm: P23443
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33623.92

構造登録者

Domsic, J.F.,Barber-Rotenberg, J.,Salami, J.,Qin, J.,Marmorstein, R. (登録日: 2014-10-17, 公開日: 2015-01-21, 最終更新日: 2023-09-20)

主引用文献

Qin, J.,Rajaratnam, R.,Feng, L.,Salami, J.,Barber-Rotenberg, J.S.,Domsic, J.,Reyes-Uribe, P.,Liu, H.,Dang, W.,Berger, S.L.,Villanueva, J.,Meggers, E.,Marmorstein, R.
Development of Organometallic S6K1 Inhibitors.
J.Med.Chem., 58:305-314, 2015

PubMed Abstract: Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previously used to target other kinases. Biochemical data demonstrate that EM5 and FL772 inhibit the kinase with IC50 value in the low nanomolar range at 100 μM ATP and that the more potent FL772 compound has a greater than 100-fold specificity over S6K2. The crystal structures of S6K1 bound to staurosporine, EM5, and FL772 reveal that the EM5 and FL772 inhibitors bind in the ATP binding pocket and make S6K1-specific contacts, resulting in changes to the p-loop, αC helix, and αD helix when compared to the staurosporine-bound structure. Cellular data reveal that FL772 is able to inhibit S6K phosphorylation in yeast cells. Together, these studies demonstrate that potent, selective, and cell permeable S6K1 inhibitors can be prepared and provide a scaffold for future development of S6K inhibitors with possible therapeutic applications.

PubMed: 25356520
DOI: 10.1021/jm5011868

実験手法

X-RAY DIFFRACTION (2.79 Å)