6LIO

Crystal structure of human PDK2 complexed with GM67520

Summary for 6LIO

• Entry DOI: 10.2210/pdb6lio/pdb
• Related: 6LIL
• Descriptor: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial, GLYCEROL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: mitochondria, kinase, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 94628.13

Authors

Kang, J.,Kim, J. (deposition date: 2019-12-12, release date: 2020-09-30, Last modification date: 2023-11-22)

Primary citation

Kang, J.,Pagire, H.S.,Kang, D.,Song, Y.H.,Lee, I.K.,Lee, K.T.,Park, C.J.,Ahn, J.H.,Kim, J.
Structural basis for the inhibition of PDK2 by novel ATP- and lipoyl-binding site targeting compounds.
Biochem.Biophys.Res.Commun., 527:778-784, 2020

PubMed Abstract: Pyruvate dehydrogenase kinase (PDK) controls the activity of pyruvate decarboxylase complex (PDC) by phosphorylating key serine residues on the E1 subunit, which leads to a decreased oxidative phosphorylation in mitochondria. Inhibition of PDK activity by natural/synthetic compounds has been shown to reverse the Warburg effect, a characteristic metabolism in cancer cells. PDK-PDC axis also has been associated with diabetes and heart disease. Therefore, regulation of PDK activity has been considered as a promising strategy to treat related diseases. Here we present the X-ray crystal structure of PDK2 complexed with a recently identified PDK4 inhibitor, compound 8c, which has been predicted to bind at the lipoyl-binding site and interrupt intermolecular interactions with the E2-E3bp subunits of PDC. The co-crystal structure confirmed the specific binding location of compound 8c and revealed the remote conformational change in the ATP-binding pocket. In addition, two novel 4,5-diarylisoxazole derivatives, GM10030 and GM67520, were synthesized and used for structural studies, which target the ATP-binding site of PDK2. These compounds bind to PDK2 with a sub-100nM affinity as determined by isothermal titration calorimetry experiments. Notably, the crystal structure of the PDK2-GM10030 complex displays unprecedented asymmetric conformation of human PDK2 dimer, especially in the ATP-lids and C-terminal tails.

PubMed: 32444142
DOI: 10.1016/j.bbrc.2020.04.102

Experimental method

X-RAY DIFFRACTION (1.76 Å)