title: Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase.
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.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shih-Chia
authors.initials: SC
authors.lastname: Tso
authors.forename: Xiangbing
authors.initials: X
authors.lastname: Qi
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Gui
authors.forename: Jacinta L
authors.initials: JL
authors.lastname: Chuang
authors.forename: Lorraine K
authors.initials: LK
authors.lastname: Morlock
authors.forename: Amy L
authors.initials: AL
authors.lastname: Wallace
authors.forename: Kamran
authors.initials: K
authors.lastname: Ahmed
authors.forename: Sunil
authors.initials: S
authors.lastname: Laxman
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Campeau
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
authors.forename: Susan M
authors.initials: SM
authors.lastname: Hutson
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Tu
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: Uttam K
authors.initials: UK
authors.lastname: Tambar
authors.forename: R Max
authors.initials: RM
authors.lastname: Wynn
authors.forename: David T
authors.initials: DT
authors.lastname: Chuang
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D007532:Isoleucine / Q000097:blood / Q000378:metabolism; D007700:Kinetics; D007930:Leucine / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D010666:Phenylpropionates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D053719:Tandem Mass Spectrometry; D014633:Valine / Q000097:blood / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D010666:Phenylpropionates; D047428:Protein Kinase Inhibitors; D007532:Isoleucine; C019521:phenylpropiolic acid; D011494:Protein Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase; D007930:Leucine; D014633:Valine
keywords: allosteric mechanisms; branched-chain α-ketoacid dehydrogenase kinase inhibitor; in vivo kinase inhibitor studies; kinase-inhibitor complex structures; structure-based inhibitor design