4H7Q

Crystal structure of branched-chain alpha-ketoacid dehydrogenase kinase in complex with alpha-ketoisocaproic acid and ADP

Summary for 4H7Q

• Entry DOI: 10.2210/pdb4h7q/pdb
• Related: 3TZ4 3TZ5 4DZY 4E00
• Descriptor: [3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial, ADENOSINE-5'-DIPHOSPHATE, 2-OXO-4-METHYLPENTANOIC ACID, ... (6 entities in total)
• Functional Keywords: ghkl protein kinase, allosteric kinase inhibitor, branched-chain alpha-ketoacid, branched-chain amino acids, maple syrup urine disease, diabetes and obesity, bergerat nucleotide-binding fold, protein kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (rat)
• Total number of polymer chains: 1
• Total formula weight: 47994.99

Authors

Tso, S.C.,Chuang, J.L.,Gui, W.J.,Wynn, R.M.,Li, J.,Chuang, D.T. (deposition date: 2012-09-20, release date: 2013-06-05, Last modification date: 2024-02-28)

Primary citation

Tso, S.C.,Qi, X.,Gui, W.J.,Chuang, J.L.,Morlock, L.K.,Wallace, A.L.,Ahmed, K.,Laxman, S.,Campeau, P.M.,Lee, B.H.,Hutson, S.M.,Tu, B.P.,Williams, N.S.,Tambar, U.K.,Wynn, R.M.,Chuang, D.T.
Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain alpha-ketoacid dehydrogenase kinase.
Proc.Natl.Acad.Sci.USA, 110:9728-9733, 2013

PubMed 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.

PubMed: 23716694
DOI: 10.1073/pnas.1303220110

Experimental method

X-RAY DIFFRACTION (2.1 Å)