2q8g

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{{STRUCTURE_2q8g| PDB=2q8g | SCENE= }}
{{STRUCTURE_2q8g| PDB=2q8g | SCENE= }}
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'''Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545'''
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===Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545===
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==Overview==
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Pyruvate dehydrogenase kinase (PDK) isoforms are molecular switches that downregulate the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation in mitochondria. We have determined structures of human PDK1 or PDK3 bound to the inhibitors AZD7545, dichloroacetate (DCA), and radicicol. We show that the trifluoromethylpropanamide end of AZD7545 projects into the lipoyl-binding pocket of PDK1. This interaction results in inhibition of PDK1 and PDK3 activities by aborting kinase binding to the PDC scaffold. Paradoxically, AZD7545 at saturating concentrations robustly increases scaffold-free PDK3 activity, similar to the inner lipoyl domain. Good DCA density is present in the helix bundle in the N-terminal domain of PDK1. Bound DCA promotes local conformational changes that are communicated to both nucleotide-binding and lipoyl-binding pockets of PDK1, leading to the inactivation of kinase activity. Finally, radicicol inhibits kinase activity by binding directly to the ATP-binding pocket of PDK3, similar to Hsp90 and Topo VI from the same ATPase/kinase superfamily.
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{{ABSTRACT_PUBMED_17683942}}
==About this Structure==
==About this Structure==
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[[Category: Mitochondrial kinase]]
[[Category: Mitochondrial kinase]]
[[Category: Pyruvate dehydrogenase complex]]
[[Category: Pyruvate dehydrogenase complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 14:31:40 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 16:52:02 2008''

Revision as of 13:52, 28 July 2008

Image:2q8g.png

Template:STRUCTURE 2q8g

Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545

Template:ABSTRACT PUBMED 17683942

About this Structure

2Q8G is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol., Kato M, Li J, Chuang JL, Chuang DT, Structure. 2007 Aug;15(8):992-1004. Epub 2007 Aug 2. PMID:17683942

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