2bu2
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Pyruvate dehydrogenase kinase (PDHK) regulates the activity of the | + | 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== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Transferred entry: 2 | + | [[Category: Transferred entry: 2 7.11 2]] |
| - | [[Category: Brown, D | + | [[Category: Brown, D G.]] |
| - | [[Category: Bungay, P | + | [[Category: Bungay, P J.]] |
| - | [[Category: Kasten, S | + | [[Category: Kasten, S A.]] |
| - | [[Category: Knoechel, T | + | [[Category: Knoechel, T R.]] |
[[Category: Phillips, C.]] | [[Category: Phillips, C.]] | ||
| - | [[Category: Robinson, C | + | [[Category: Robinson, C M.]] |
| - | [[Category: Roche, T | + | [[Category: Roche, T E.]] |
[[Category: Taylor, W.]] | [[Category: Taylor, W.]] | ||
| - | [[Category: Tucker, A | + | [[Category: Tucker, A D.]] |
[[Category: ATP]] | [[Category: ATP]] | ||
[[Category: MG]] | [[Category: MG]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:41:42 2008'' |
Revision as of 14:41, 21 February 2008
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CRYSTAL STRUCTURES OF HUMAN PYRUVATE DEHYDROGENASE KINASE 2 CONTAINING PHYSIOLOGICAL AND SYNTHETIC LIGANDS
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 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
2BU2 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Transferred entry: 2.7.11.2, with EC number 2.7.1.99 Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
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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