ジャーナル: Structure / 年: 2021 タイトル: Molecular structures of human ACAT2 disclose mechanism for selective inhibition. 著者: Tao Long / Yang Liu / Xiaochun Li / 要旨: Endoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored ...Endoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored in cytosolic lipid droplets. Selective inhibition of ACAT2 has been shown to considerably attenuate hypercholesterolemia and atherosclerosis in mice. Here, we report cryogenic electron microscopy structures of human ACAT2 bound to its specific inhibitor pyripyropene A or the general ACAT inhibitor nevanimibe. Structural analysis reveals that ACAT2 has a topology in membranes similar to that of ACAT1. A catalytic core with an entry site occupied by a cholesterol molecule and another site for allosteric activation of ACAT2 is observed in these structures. Enzymatic assays show that mutations within sites of cholesterol entry or allosteric activation attenuate ACAT2 activity in vitro. Together, these results reveal mechanisms for ACAT2-mediated esterification of cholesterol, providing a blueprint to design new ACAT2 inhibitors for use in the prevention of cardiovascular disease.
履歴
登録
2021年6月8日
登録サイト: RCSB / 処理サイト: RCSB
改定 1.0
2021年9月22日
Provider: repository / タイプ: Initial release
改定 1.1
2024年5月29日
Group: Data collection / カテゴリ: chem_comp_atom / chem_comp_bond