2q8h
From Proteopedia
(New page: 200px<br /> <applet load="2q8h" size="450" color="white" frame="true" align="right" spinBox="true" caption="2q8h, resolution 2.00Å" /> '''Structure of pyruva...) |
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| - | [[Image:2q8h.gif|left|200px]]<br /> | + | [[Image:2q8h.gif|left|200px]]<br /><applet load="2q8h" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="2q8h, resolution 2.00Å" /> | caption="2q8h, resolution 2.00Å" /> | ||
'''Structure of pyruvate dehydrogenase kinase isoform 1 in complex with dichloroacetate (DCA)'''<br /> | '''Structure of pyruvate dehydrogenase kinase isoform 1 in complex with dichloroacetate (DCA)'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2Q8H 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 K and TF4 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/[Pyruvate_dehydrogenase_(acetyl-transferring)]_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.2 2.7.11.2] Full crystallographic information is available from [http:// | + | 2Q8H 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 <scene name='pdbligand=K:'>K</scene> and <scene name='pdbligand=TF4:'>TF4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/[Pyruvate_dehydrogenase_(acetyl-transferring)]_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.2 2.7.11.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q8H OCA]. |
==Reference== | ==Reference== | ||
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[[Category: pyruvate dehydrogenase complex]] | [[Category: pyruvate dehydrogenase complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:50:06 2008'' |
Revision as of 11:50, 23 January 2008
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Structure of pyruvate dehydrogenase kinase isoform 1 in complex with dichloroacetate (DCA)
Overview
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.
About this Structure
2Q8H is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as [Pyruvate_dehydrogenase_(acetyl-transferring)_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number 2.7.11.2 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[[Category: [Pyruvate dehydrogenase (acetyl-transferring)] kinase]]
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