2BU8
crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands
Summary for 2BU8
Entry DOI | 10.2210/pdb2bu8/pdb |
Related | 2BTZ 2BU2 2BU5 2BU6 2BU7 |
Descriptor | PYRUVATE DEHYDROGENASE KINASE ISOENZYME 2, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total) |
Functional Keywords | transferase, pyruvate dehydrogenase kinase 2 ghkl motif regulation |
Biological source | HOMO SAPIENS (HUMAN) |
Total number of polymer chains | 1 |
Total formula weight | 45228.18 |
Authors | Knoechel, T.R.,Tucker, A.D.,Robinson, C.M.,Phillips, C.,Taylor, W.,Bungay, P.J.,Kasten, S.A.,Roche, T.E.,Brown, D.G. (deposition date: 2005-06-08, release date: 2006-02-02, Last modification date: 2023-12-13) |
Primary citation | Knoechel, T.R.,Tucker, A.D.,Robinson, C.M.,Phillips, C.,Taylor, W.,Bungay, P.J.,Kasten, S.A.,Roche, T.E.,Brown, D.G. Regulatory Roles of the N-Terminal Domain Based on Crystal Structures of Human Pyruvate Dehydrogenase Kinase 2 Containing Physiological and Synthetic Ligands. Biochemistry, 45:402-, 2006 Cited by PubMed 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 beta and gamma 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 binding site that is located at one end of the R domain. Pfz3 (an allosteric inhibitor) binds in an extended site at the other end of the R domain. We conclude that the N-terminal domain of PDHK has a key regulatory function and propose that the different inhibitor classes act by discrete mechanisms. The structures we describe provide insights that can be used for structure-based design of PDHK inhibitors. PubMed: 16401071DOI: 10.1021/BI051402S PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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