PDBsum entry 2q8h

Transferase

PDB id: 2q8h

Contents

Protein chain

365 a.a. *

Ligands

TF4

Metals

__K

Waters ×242

* Residue conservation analysis

PDB id:

2q8h

Name:

Transferase

Title:

Structure of pyruvate dehydrogenase kinase isoform 1 in complex with dichloroacetate (dca)

Structure:

[Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1. Chain: a. Synonym: pyruvate dehydrogenase kinase isoform 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pdk1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Resolution:

2.00Å R-factor: 0.232 R-free: 0.277

Authors:

M.Kato,J.Li,J.L.Chuang,D.T.Chuang

Key ref:

M.Kato et al. (2007). Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure, 15, 992. PubMed id: 17683942 DOI: 10.1016/j.str.2007.07.001

Date:

10-Jun-07 Release date: 24-Jul-07

Protein chain

Q15118  (PDK1_HUMAN) -  [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial from Homo sapiens

Seq: 436 a.a.

Struc: 365 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.2 - [pyruvate dehydrogenase (acetyl-transferring)] kinase.
• Reaction: L-seryl-[pyruvate dehydrogenase E1 alpha subunit] + ATP = O-phospho-L- seryl-[pyruvate dehydrogenase E1 alpha subunit] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.str.2007.07.001

Structure 15:992 (2007)

PubMed id: 17683942

Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol.

M.Kato, J.Li, J.L.Chuang, D.T.Chuang.

ABSTRACT

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.

Selected figure(s)

Figure 1.
Figure 1.

Figure 6.
Figure 6. Structure of the Radicicol-Binding Site in PDK3-L2
(A) The omit electron density map of radicicol bound to PDK3. The density is superimposed on the refined model of radicicol at the 3σ level in blue and the 9σ level in red.
(B) Interactions between PDK3 residues and radicicol. H bonds are indicated by dashed lines. Water molecules are depicted as red balls.
(C) Comparison between radicicol and ATP bound to PDK3. The structure of PDK3-L2-ATP (PDB ID code 1Y8P; Kato et al., 2005) (magenta) is superimposed on PDK3-L2-radicicol (cyan).
(D) Superimposition of radicicol molecules bound to PDK1 (cyan), Hsp90 (PDB ID code 1BGQ; Roe et al., 1999) (pink), and Topo VI (PDB ID code 2HKJ; Corbett and Berger, 2005) (yellow). The three structures were superimposed based on the corresponding residues shown in the figure. Stereo figures of (B)–(D) are provided in Figure S4.
(E) Comparison of the shape of the radicicol-binding pockets of PDK3, Hsp90, and Topo VI. The electrostatic surface of each protein is shown with the negative charge in red and the positive charge in blue.

The above figures are reprinted by permission from Cell Press: Structure (2007, 15, 992-0) copyright 2007.

Figures were selected by an automated process.