2BU5

crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands

Summary for 2BU5

• Entry DOI: 10.2210/pdb2bu5/pdb
• Related: 2BTZ 2BU2 2BU6 2BU7 2BU8
• Descriptor: PYRUVATE DEHYDROGENASE KINASE ISOENZYME 2, 4-({(2R,5S)-2,5-DIMETHYL-4-[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]PIPERAZIN-1-YL}CARBONYL)BENZONITRILE (3 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: 45031.10

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

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: 16401071
DOI: 10.1021/BI051402S

Experimental method

X-RAY DIFFRACTION (2.35 Å)