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2BU8

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

Summary for 2BU8
Entry DOI10.2210/pdb2bu8/pdb
Related2BTZ 2BU2 2BU5 2BU6 2BU7
DescriptorPYRUVATE DEHYDROGENASE KINASE ISOENZYME 2, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
Functional Keywordstransferase, pyruvate dehydrogenase kinase 2 ghkl motif regulation
Biological sourceHOMO SAPIENS (HUMAN)
Total number of polymer chains1
Total formula weight45228.18
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 citationKnoechel, 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: 16401071
DOI: 10.1021/BI051402S
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.5 Å)
Structure validation

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