Literature summary for 2.7.11.2 extracted from

Kukimoto-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 (2011), Acta Crystallogr. Sect. D, 67, 763-773.

Application

Application	Comment	Organism
drug development	development of specific inhibitors of PDK4 has become an especially important focus for the pharmaceutical management of diabetes and obesity	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
isozyme PDK4 complexed with either AMPPNP, ADP or inhibitor M77976, screening using the sitting drop vapour diffusion method at 20°C, optimized hanging drop vapour diffusion method mixing PDK4 with 10 mM MgCl2, and 5 mM AMPPNP, the reservoir solution contains 1.7 M ammonium sulfate, 2% PEG 400, and Na HEPES, pH 7.1, soaking the PDK4-AMPPNP crystals in 5 mM ADP or 1 mM M77976, X-ray diffraction structure determination and analysis at 1.85-2.53 A resolution, molecular replacement using rat PDK2, PDB entry 1jm6, modeling	Homo sapiens

Crystallization (Comment)

Organism

isozyme PDK4 complexed with either AMPPNP, ADP or inhibitor M77976, screening using the sitting drop vapour diffusion method at 20°C, optimized hanging drop vapour diffusion method mixing PDK4 with 10 mM MgCl2, and 5 mM AMPPNP, the reservoir solution contains 1.7 M ammonium sulfate, 2% PEG 400, and Na HEPES, pH 7.1, soaking the PDK4-AMPPNP crystals in 5 mM ADP or 1 mM M77976, X-ray diffraction structure determination and analysis at 1.85-2.53 A resolution, molecular replacement using rat PDK2, PDB entry 1jm6, modeling

Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
4-[4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl]benzene-1,3-diol	inhibitor 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	Homo sapiens
radicicol	-	Homo sapiens

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Homo sapiens

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q16654	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
ATP + Ac-YHGHSMSDPGVSYR	-	Homo sapiens	ADP + [Ac-YHGHSMSDPGVSYR]phosphate	-	?

Synonyms

Synonyms	Comment	Organism
PDK4	-	Homo sapiens
pyruvate dehydrogenase kinase 4	-	Homo sapiens

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
8	-	assay at	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
ATP	binding structure with isozyme PDK4, detailed overview	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor	Structure
0.648	-	pH 8.0, temperature not specified in the publication	Homo sapiens	4-[4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl]benzene-1,3-diol
1.079	-	pH 8.0, temperature not specified in the publication	Homo sapiens	radicicol

General Information

General Information	Comment	Organism
metabolism	the mitochondrial pyruvate dehydrogenase complex, PDC, activity is tightly regulated by four members of a family of pyruvate dehydrogenase kinase isoforms, PDK1-4, which phosphorylate and inactivate PDC	Homo sapiens
additional information	ADP-bound PDK4 has a slightly wider active-site cleft and a more disordered ATP lid compared with AMPPNP-bound PDK4, binding structures of ADP and AMPPNP to isozyme PDK4, detailed overview. The width of the active-site cleft of PDK4 is determined by the location of the Tyr332 side chain	Homo sapiens