8EGD

Branched chain ketoacid dehydrogenase kinase in complex with inhibitor

8EGD の概要

• エントリーDOI: 10.2210/pdb8egd/pdb
• 分子名称: [3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: branched-chain ketoacid dehydrogenase, branched-chain ketoacid dehydrogenase kinase, inhibitors, angiotensin receptor blocker, complex, signaling protein
• 由来する生物種: Rattus norvegicus (Norway rat)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45568.90

構造登録者

Liu, S. (登録日: 2022-09-12, 公開日: 2023-03-08, 最終更新日: 2023-10-25)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.047 Å)