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2ZDX

Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4

Summary for 2ZDX
Entry DOI10.2210/pdb2zdx/pdb
Related2ZDY
DescriptorPyruvate dehydrogenase kinase isozyme 4, 4-[4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl]benzene-1,3-diol (3 entities in total)
Functional Keywordspdk4, kinase, atp-binding, inhibitor, carbohydrate metabolism, glucose metabolism, mitochondrion, phosphoprotein, transferase, transit peptide
Biological sourceHomo sapiens (Human)
Cellular locationMitochondrion matrix: Q16654
Total number of polymer chains2
Total formula weight90134.63
Authors
Kawamoto, M.,Shiromizu, I.,Kukimoto-niino, M.,Tokmakov, A.,Terada, T.,Shirouzu, M.,Matsusue, T.,Yokoyama, S. (deposition date: 2007-11-30, release date: 2008-12-09, Last modification date: 2023-11-01)
Primary citationKukimoto-Niino, M.,Tokmakov, A.,Terada, T.,Ohbayashi, N.,Fujimoto, T.,Gomi, S.,Shiromizu, I.,Kawamoto, M.,Matsusue, T.,Shirouzu, M.,Yokoyama, S.
Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4.
Acta Crystallogr.,Sect.D, 67:763-773, 2011
Cited by
PubMed Abstract: 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.
PubMed: 21904029
DOI: 10.1107/S090744491102405X
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.54 Å)
Structure validation

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