PDBsum entry 2bu7

Transferase

PDB id: 2bu7

Contents

Protein chain

359 a.a.

Ligands

TF3

Waters ×152

References listed in PDB file

Key reference

• Title: Regulatory roles of the n-Terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands.
• 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.
• Ref.: Biochemistry, 2006, 45, 402-415. [DOI no: 10.1021/bi051402s]
• PubMed id: 16401071

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.