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

Shih Chia Tso, Xiangbing Qi, Wen Jun Gui, Jacinta L. Chuang, Lorraine K. Morlock, Amy L. Wallace, Kamran Ahmed, Sunil Laxman, Philippe M. Campeau, Brendan H. Lee, Susan M. Hutson, Benjamin P. Tu, Noelle S. Williams, Uttam K. Tambar, R. Max Wynn, David T. Chuang

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)9728-9733
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number24
DOIs
StatePublished - Jun 11 2013

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Keywords

  • Allosteric mechanisms
  • Branched-chain α-ketoacid dehydrogenase kinase inhibitor
  • In vivo kinase inhibitor studies
  • Kinase-inhibitor complex structures
  • Structure-based inhibitor design

ASJC Scopus subject areas

  • General

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