TY - JOUR
T1 - Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase
AU - Tso, Shih Chia
AU - Qi, Xiangbing
AU - Gui, Wen Jun
AU - Chuang, Jacinta L.
AU - Morlock, Lorraine K.
AU - Wallace, Amy L.
AU - Ahmed, Kamran
AU - Laxman, Sunil
AU - Campeau, Philippe M.
AU - Lee, Brendan H.
AU - Hutson, Susan M.
AU - Tu, Benjamin P.
AU - Williams, Noelle S.
AU - Tambar, Uttam K.
AU - Wynn, R. Max
AU - Chuang, David T.
PY - 2013/6/11
Y1 - 2013/6/11
N2 - 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.
AB - 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.
KW - Allosteric mechanisms
KW - Branched-chain α-ketoacid dehydrogenase kinase inhibitor
KW - In vivo kinase inhibitor studies
KW - Kinase-inhibitor complex structures
KW - Structure-based inhibitor design
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U2 - 10.1073/pnas.1303220110
DO - 10.1073/pnas.1303220110
M3 - Article
C2 - 23716694
AN - SCOPUS:84878983057
SN - 0027-8424
VL - 110
SP - 9728
EP - 9733
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -