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

Index: Proc. Natl. Acad. Sci. U. S. A. 110(24) , 9728-33, (2013)

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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.