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rdf:type |
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lifeskim:mentions |
umls-concept:C0023688,
umls-concept:C0035820,
umls-concept:C0043655,
umls-concept:C0086418,
umls-concept:C0205463,
umls-concept:C0220905,
umls-concept:C0332256,
umls-concept:C0444626,
umls-concept:C1514562,
umls-concept:C1527178,
umls-concept:C1705938,
umls-concept:C1880389,
umls-concept:C1883204,
umls-concept:C1883221,
umls-concept:C1883254
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pubmed:issue |
2
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pubmed:dateCreated |
2006-1-10
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pubmed:databankReference |
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pubmed:abstractText |
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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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0006-2960
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
17
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pubmed:volume |
45
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
402-15
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:16401071-Adenosine Triphosphate,
pubmed-meshheading:16401071-Amino Acid Sequence,
pubmed-meshheading:16401071-Binding Sites,
pubmed-meshheading:16401071-Crystallography, X-Ray,
pubmed-meshheading:16401071-Dichloroacetate,
pubmed-meshheading:16401071-Dimerization,
pubmed-meshheading:16401071-Humans,
pubmed-meshheading:16401071-Isoenzymes,
pubmed-meshheading:16401071-Ligands,
pubmed-meshheading:16401071-Magnesium,
pubmed-meshheading:16401071-Models, Molecular,
pubmed-meshheading:16401071-Molecular Sequence Data,
pubmed-meshheading:16401071-Peptide Fragments,
pubmed-meshheading:16401071-Protein Binding,
pubmed-meshheading:16401071-Protein Kinases,
pubmed-meshheading:16401071-Protein Structure, Tertiary,
pubmed-meshheading:16401071-Protein-Serine-Threonine Kinases,
pubmed-meshheading:16401071-Water
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pubmed:year |
2006
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pubmed:articleTitle |
Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands.
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pubmed:affiliation |
PGRD Sandwich, Pfizer Ltd, Sandwich, Kent CT139NJ, United Kingdom.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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