2bu7: Difference between revisions

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[[Image:2bu7.gif|left|200px]]
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[[Image:2bu7.png|left|200px]]


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{{STRUCTURE_2bu7|  PDB=2bu7  |  SCENE=  }}  
{{STRUCTURE_2bu7|  PDB=2bu7  |  SCENE=  }}  


'''CRYSTAL STRUCTURES OF HUMAN PYRUVATE DEHYDROGENASE KINASE 2 CONTAINING PHYSIOLOGICAL AND SYNTHETIC LIGANDS'''
===CRYSTAL STRUCTURES OF HUMAN PYRUVATE DEHYDROGENASE KINASE 2 CONTAINING PHYSIOLOGICAL AND SYNTHETIC LIGANDS===




==Overview==
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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.
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{{ABSTRACT_PUBMED_16401071}}


==About this Structure==
==About this Structure==
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[[Category: Pyruvate dehydrogenase kinase 2 ghkl motif regulation]]
[[Category: Pyruvate dehydrogenase kinase 2 ghkl motif regulation]]
[[Category: Transferase]]
[[Category: Transferase]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 20:48:13 2008''
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 07:47:13 2008''

Revision as of 04:47, 28 July 2008

File:2bu7.png

Template:STRUCTURE 2bu7

CRYSTAL STRUCTURES OF HUMAN PYRUVATE DEHYDROGENASE KINASE 2 CONTAINING PHYSIOLOGICAL AND SYNTHETIC LIGANDS

Template:ABSTRACT PUBMED 16401071

About this Structure

2BU7 is a Single protein structure of sequence from Homo sapiens. 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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