期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 24, 页码 9728-9733出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1303220110
关键词
branched-chain alpha-ketoacid dehydrogenase kinase inhibitor; structure-based inhibitor design; allosteric mechanisms; kinase-inhibitor complex structures; in vivo kinase inhibitor studies
资金
- National Institutes of Health [DK62306, DK26758, DK92921]
- Welch Foundation [I-1286]
- Department of Energy Contract [DE-AC02-06CH11357]
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 a-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)-alpha-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.
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