Structure of Nevanimibe-bound Tetrameric Human Sterol O-acyltransferase 1

Cholesterol is physiologically indispensable for mammals, as illustrated by its abundance of up to 50% of plasma membrane lipids; in contrast, only 5% of lipids in the endoplasmic reticulum (ER) are cholesterol 1 . The ER enzyme sterol O-acyltransferase 1 (also named acyl-coA:cholesterol acyltransferase, ACAT1) transfers a long chain fatty acid to cholesterol to form cholesteryl esters that coalesce into cytosolic lipid droplets. Under conditions of cholesterol overload, ACAT1 maintains the low cholesterol concentration of the ER and thereby plays an essential role in cholesterol homeostasis 2 , 3 . Notably, ACAT1 is implicated in Alzheimer’s disease 4 , atherosclerosis 5 , and cancers 6 . Here, we report a cryo-EM structure of human ACAT1 in complex with nevanimibe 7 , an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The holoenzyme is a tetramer made up of two homodimers. Each ACAT1 monomer harbors nine transmembrane helices (TMs). Nevanimibe and an endogenous acyl-CoA are observed in a cavity created by TMs 4–9. The cavity contains a histidine previously shown to be required for catalytic activity. Our structural data along with biochemical analysis provide a physical model to explain the process of cholesterol esterification. This work also provides interaction details between nevanimibe and ACAT1 to accelerate the development of ACAT1 inhibitors to treat related diseases.