Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9728-33. doi: 10.1073/pnas.1303220110. Epub 2013 May 28.

Abstract

The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are elevated in maple syrup urine disease, heart failure, obesity, and type 2 diabetes. BCAA homeostasis is controlled by the mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC), which is negatively regulated by the specific BCKD kinase (BDK). Here, we used structure-based design to develop a BDK inhibitor, (S)-α-chloro-phenylpropionic acid [(S)-CPP]. Crystal structures of the BDK-(S)-CPP complex show that (S)-CPP binds to a unique allosteric site in the N-terminal domain, triggering helix movements in BDK. These conformational changes are communicated to the lipoyl-binding pocket, which nullifies BDK activity by blocking its binding to the BCKDC core. Administration of (S)-CPP to mice leads to the full activation and dephosphorylation of BCKDC with significant reduction in plasma BCAA concentrations. The results buttress the concept of targeting mitochondrial BDK as a pharmacological approach to mitigate BCAA accumulation in metabolic diseases and heart failure.

Keywords: allosteric mechanisms; branched-chain α-ketoacid dehydrogenase kinase inhibitor; in vivo kinase inhibitor studies; kinase-inhibitor complex structures; structure-based inhibitor design.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Binding Sites / genetics
  • Chromatography, Liquid
  • Crystallography, X-Ray
  • Isoleucine / blood
  • Isoleucine / metabolism
  • Kinetics
  • Leucine / blood
  • Leucine / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mitochondrial Proteins / antagonists & inhibitors
  • Mitochondrial Proteins / chemistry*
  • Mitochondrial Proteins / metabolism
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Phenylpropionates / chemistry
  • Phenylpropionates / metabolism
  • Phenylpropionates / pharmacology
  • Phosphorylation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / chemistry*
  • Protein Kinases / metabolism
  • Protein Structure, Tertiary*
  • Tandem Mass Spectrometry
  • Valine / blood
  • Valine / metabolism

Substances

  • Mitochondrial Proteins
  • Phenylpropionates
  • Protein Kinase Inhibitors
  • Isoleucine
  • phenylpropiolic acid
  • Protein Kinases
  • (3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase
  • Leucine
  • Valine

Associated data

  • PDB/3TZ0
  • PDB/3TZ2
  • PDB/3TZ4
  • PDB/3TZ5
  • PDB/4DZY
  • PDB/4H7Q
  • PDB/4H81
  • PDB/4H85