Regulatory Roles of the N-Terminal Domain Based on Crystal Structures of Human Pyruvate Dehydrogenase Kinase 2 Containing Physiological and Synthetic Ligands†,‡

TLDR: It is concluded that the N-terminal domain of PDHK has a key regulatory function and proposed that the different inhibitor classes act by discrete mechanisms.

Abstract: Pyruvate dehydrogenase kinase (PDHK) regulates the activity of the pyruvate dehydrogenase multienzyme complex. PDHK inhibition provides a route for therapeutic intervention in diabetes and cardiovascular disorders. We report crystal structures of human PDHK isozyme 2 complexed with physiological and synthetic ligands. Several of the PDHK2 structures disclosed have C-terminal cross arms that span a large trough region between the N-terminal regulatory (R) domains of the PDHK2 dimers. The structures containing bound ATP and ADP demonstrate variation in the conformation of the active site lid, residues 316−321, which enclose the nucleotide β and γ phosphates at the active site in the C-terminal catalytic domain. We have identified three novel ligand binding sites located in the R domain of PDHK2. Dichloroacetate (DCA) binds at the pyruvate binding site in the center of the R domain, which together with ADP, induces significant changes at the active site. Nov3r and AZ12 inhibitors bind at the lipoamide bindin...