9BR7

Crystal structure of human succinyl-CoA:glutarate-CoA transferase (SUGCT) in complex with Losartan carboxylic acid

これはPDB形式変換不可エントリーです。

9BR7 の概要

• エントリーDOI: 10.2210/pdb9br7/pdb
• 分子名称: Succinate--hydroxymethylglutarate CoA-transferase, losartan carboxylic acid, AMMONIUM ION, ... (5 entities in total)
• 機能のキーワード: sugct, succinyl-coa, glutarate, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 181069.97

構造登録者

Wu, R.,Lazarus, M.B. (登録日: 2024-05-10, 公開日: 2024-08-07)

主引用文献

Wu, R.,Khamrui, S.,Dodatko, T.,Leandro, J.,Sabovic, A.,Violante, S.,Cross, J.R.,Marsan, E.,Kumar, K.,DeVita, R.J.,Lazarus, M.B.,Houten, S.M.
Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1.
Acs Chem.Biol., 19:1544-1553, 2024

PubMed Abstract: Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or nontoxic metabolites. Here, we report a putative novel target, succinyl-CoA:glutarate-CoA transferase (SUGCT), which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA and the derived 3-hydroxyglutaric acid. SUGCT is a type III CoA transferase that uses succinyl-CoA and glutaric acid as substrates. We report the structure of SUGCT, develop enzyme- and cell-based assays, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme in a high-throughput screen of FDA-approved compounds. The cocrystal structure of SUGCT with losartan carboxylic acid revealed a novel pocket in the active site and further validated the high-throughput screening approach. These results may form the basis for the future development of new pharmacological intervention to treat GA1.

PubMed: 38915184
DOI: 10.1021/acschembio.4c00204

実験手法

X-RAY DIFFRACTION (2.08 Å)