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==Overview== | ==Overview== | ||
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 ... | 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. | ||
==About this Structure== | ==About this Structure== | ||
2BU2 is a | 2BU2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, ATP and TF1 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.2 Transferred entry: 2.7.11.2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.99 2.7.1.99] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2BU2 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
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Revision as of 14:07, 5 November 2007
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CRYSTAL STRUCTURES OF HUMAN PYRUVATE DEHYDROGENASE KINASE 2 CONTAINING PHYSIOLOGICAL AND SYNTHETIC LIGANDS
OverviewOverview
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.
About this StructureAbout this Structure
2BU2 is a Single protein structure of sequence from Homo sapiens with MG, ATP and TF1 as ligands. Active as Transferred entry: 2.7.11.2, with EC number 2.7.1.99 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands., Knoechel TR, Tucker AD, Robinson CM, Phillips C, Taylor W, Bungay PJ, Kasten SA, Roche TE, Brown DG, Biochemistry. 2006 Jan 17;45(2):402-15. PMID:16401071
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