PDBsum entry 2bu7

Transferase

PDB id: 2bu7

Contents

Protein chain

359 a.a. *

Ligands

TF3

Waters ×152

* Residue conservation analysis

PDB id:

2bu7

Name:

Transferase

Title:

Crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands

Structure:

Pyruvate dehydrogenase kinase isoenzyme 2. Chain: a. Synonym: pyruvate dehydrogenase kinase isoform 2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: high five.

Biol. unit:

Dimer (from PDB file)

Resolution:

2.40Å R-factor: 0.211 R-free: 0.241

Authors:

T.R.Knoechel,A.D.Tucker,C.M.Robinson,C.Phillips,W.Taylor,P.J.Bungay, S.A.Kasten,T.E.Roche,D.G.Brown

Key ref:

T.R.Knoechel et al. (2006). Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry, 45, 402-415. PubMed id: 16401071 DOI: 10.1021/bi051402s

Date:

08-Jun-05 Release date: 02-Feb-06

Protein chain

Q15119  (PDK2_HUMAN) -  [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial from Homo sapiens

Seq: 407 a.a.

Struc: 359 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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: 10.1021/bi051402s

Biochemistry 45:402-415 (2006)

PubMed id: 16401071

Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands.

T.R.Knoechel, A.D.Tucker, C.M.Robinson, C.Phillips, W.Taylor, P.J.Bungay, S.A.Kasten, T.E.Roche, D.G.Brown.

ABSTRACT

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.