3TVW

Crystal Structure of the humanized carboxyltransferase domain of yeast Acetyl-coA caroxylase in complex with compound 4

3TVW の概要

• エントリーDOI: 10.2210/pdb3tvw/pdb
• 分子名称: Acetyl-CoA carboxylase, [4-(2H-chromen-3-ylmethyl)piperazin-1-yl]-[3-(1H-pyrazol-5-yl)phenyl]methanone (3 entities in total)
• 機能のキーワード: carboxyltransferase, ligase
• 由来する生物種: Saccharomyces cerevisiae S288c (Baker's yeast)
• 細胞内の位置: Cytoplasm: Q00955
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 262863.95

構造登録者

Rajamohan, F.,Marr, E.,Reyes, A.,Landro, J.A.,Anderson, M.D.,Corbett, J.W.,Dirico, K.J.,Harwood, J.H.,Tu, M.,Vajdos, F.F. (登録日: 2011-09-20, 公開日: 2011-10-19, 最終更新日: 2023-09-13)

主引用文献

Rajamohan, F.,Marr, E.,Reyes, A.R.,Landro, J.A.,Anderson, M.D.,Corbett, J.W.,Dirico, K.J.,Harwood, J.H.,Tu, M.,Vajdos, F.F.
Structure-guided Inhibitor Design for Human Acetyl-coenzyme A Carboxylase by Interspecies Active Site Conversion.
J.Biol.Chem., 286:41510-41519, 2011

PubMed Abstract: Inhibition of acetyl-CoA carboxylases (ACCs), a crucial enzyme for fatty acid metabolism, has been shown to promote fatty acid oxidation and reduce body fat in animal models. Therefore, ACCs are attractive targets for structure-based inhibitor design, particularly the carboxyltransferase (CT) domain, which is the primary site for inhibitor interaction. We have cloned, expressed, and purified the CT domain of human ACC2 using baculovirus-mediated insect cell expression system. However, attempts to crystallize the human ACC2 CT domain have not been successful in our hands. Hence, we have been using the available crystal structure of yeast CT domain to design human ACC inhibitors. Unfortunately, as the selectivity of the lead series has increased against the full-length human enzyme, the potency against the yeast enzyme has decreased significantly. This loss of potency against the yeast enzyme correlated with a complete lack of binding of the human-specific compounds to crystals of the yeast CT domain. Here, we address this problem by converting nine key active site residues of the yeast CT domain to the corresponding human residues. The resulting humanized yeast ACC-CT (yCT-H9) protein exhibits biochemical and biophysical properties closer to the human CT domain and binding to human specific compounds. We report high resolution crystal structures of yCT-H9 complexed with inhibitors that show a preference for the human CT domain. These structures offer insights that explain the species selectivity of ACC inhibitors and may guide future drug design programs.

PubMed: 21953464
DOI: 10.1074/jbc.M111.275396

実験手法

X-RAY DIFFRACTION (2.8 Å)