8EGF

Branched chain ketoacid dehydrogenase kinase in complex with inhibitor

Summary for 8EGF

• Entry DOI: 10.2210/pdb8egf/pdb
• Related: 8EGD
• Descriptor: [3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial, ADENOSINE-5'-DIPHOSPHATE, POTASSIUM ION, ... (6 entities in total)
• Functional Keywords: branched-chain ketoacid dehydrogenase, branched-chain ketoacid dehydrogenase kinase, inhibitors, angiotensin receptor blocker, complex, signaling protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 1
• Total formula weight: 45488.61

Authors

Liu, S. (deposition date: 2022-09-12, release date: 2023-03-08, Last modification date: 2023-10-25)

Primary citation

Liu, S.,Kormos, B.L.,Knafels, J.D.,Sahasrabudhe, P.V.,Rosado, A.,Sommese, R.F.,Reyes, A.R.,Ward, J.,Roth Flach, R.J.,Wang, X.,Buzon, L.M.,Reese, M.R.,Bhattacharya, S.K.,Omoto, K.,Filipski, K.J.
Structural studies identify angiotensin II receptor blocker-like compounds as branched-chain ketoacid dehydrogenase kinase inhibitors.
J.Biol.Chem., 299:102959-102959, 2023

PubMed Abstract: The mammalian mitochondrial branched-chain ketoacid dehydrogenase (BCKD) complex is a multienzyme complex involved in the catabolism of branched-chain amino acids. BCKD is regulated by the BCKD kinase, or BCKDK, which binds to the E2 subunit of BCKD, phosphorylates its E1 subunit, and inhibits enzymatic activity. Inhibition of the BCKD complex results in increased levels of branched-chain amino acids and branched-chain ketoacids, and this buildup has been associated with heart failure, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. To find BCKDK inhibitors for potential treatment of these diseases, we performed both NMR and virtual fragment screening and identified tetrazole-bearing fragments that bind BCKDK at multiple sites. Through structure-based virtual screening expanding from these fragments, the angiotensin receptor blocker class antihypertension drugs and angiotensin receptor blocker-like compounds were discovered to be potent BCKDK inhibitors, suggesting potential new avenues for heart failure treatment combining BCKDK inhibition and antihypertension.

PubMed: 36717078
DOI: 10.1016/j.jbc.2023.102959

Experimental method

X-RAY DIFFRACTION (1.85 Å)