4RLO
Human p70s6k1 with ruthenium-based inhibitor EM5
Summary for 4RLO
| Entry DOI | 10.2210/pdb4rlo/pdb |
| Related | 4RLP |
| Descriptor | Ribosomal protein S6 kinase beta-1, [(amino-kappaN)methanethiolato](3-fluoro-9-hydroxypyrido[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dionato-kappa~2~N,N')(1,4,7-trithionane-kappa~3~S~1~,S~4~,S~7~)ruthenium, GLYCEROL, ... (8 entities in total) |
| Functional Keywords | kinase, 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 | 2 |
| Total formula weight | 67271.23 |
| Authors | Domsic, J.F.,Barber-Rotenberg, J.,Salami, J.,Qin, J.,Marmorstein, R. (deposition date: 2014-10-17, release date: 2015-01-21, Last modification date: 2023-09-20) |
| Primary citation | 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 Cited by 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: 25356520DOI: 10.1021/jm5011868 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.527 Å) |
Structure validation
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