M77976
目录号 : GC60232M77976 是一种特异性的,ATP 竞争性的丙酮酸脱氢酶激酶 PDK4 抑制剂,其作用的 IC50 值为 648 μM。M77976 有用于肥胖症和糖尿病研究的潜力。
Cas No.:394237-61-7
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M77976 is a specific ATP-competitive inhibitor of PDK4 (pyruvate dehydrogenase kinase isoforms 4), with an IC50 of 648 μM. M77976 is potential for the research of obesity and diabetes[1].
M77976 binds to the ATP-binding pocket of PDK4 and causes local conformational changes with complete disordering of the ATP lid[1].M77976 makes hydrophobic interactions with the side chains of Asn258, Ala262, Val298, Leu306 and Thr358 of PDK4[1].
[1]. Kukimoto-Niino M, et al. Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4. Acta Crystallogr D Biol Crystallogr. 2011 Sep;67(Pt 9):763-73.
Cas No. | 394237-61-7 | SDF | |
Canonical SMILES | COC1=CC=C(C=C1)C2=C(NN=C2C3=CC=C(C=C3O)O)C | ||
分子式 | C17H16N2O3 | 分子量 | 296.32 |
溶解度 | DMSO: 250 mg/mL (843.68 mM) | 储存条件 | Store at -20°C |
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Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4
Acta Crystallogr D Biol Crystallogr 2011 Sep;67(Pt 9):763-73.PMID:21904029DOI:10.1107/S090744491102405X
The mitochondrial pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. PDC activity is tightly regulated by four members of a family of pyruvate dehydrogenase kinase isoforms (PDK1-4), which phosphorylate and inactivate PDC. Recently, the development of specific inhibitors of PDK4 has become an especially important focus for the pharmaceutical management of diabetes and obesity. In this study, crystal structures of human PDK4 complexed with either AMPPNP, ADP or the inhibitor M77976 were determined. ADP-bound PDK4 has a slightly wider active-site cleft and a more disordered ATP lid compared with AMPPNP-bound PDK4, although both forms of PDK4 assume open conformations with a wider active-site cleft than that in the closed conformation of the previously reported ADP-bound PDK2 structure. M77976 binds to the ATP-binding pocket of PDK4 and causes local conformational changes with complete disordering of the ATP lid. M77976 binding also leads to a large domain rearrangement that further expands the active-site cleft of PDK4 compared with the ADP- and AMPPNP-bound forms. Biochemical analyses revealed that M77976 inhibits PDK4 with increased potency compared with the previously characterized PDK inhibitor radicicol. Thus, the present structures demonstrate for the first time the flexible and dynamic aspects of PDK4 in the open conformation and provide a basis for the development of novel inhibitors targeting the nucleotide-binding pocket of PDK4.