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

By T. Long, Yingyuan Sun, Abdirahman Hassan, Xiaofeng Qi, Xiaochun Li. 2020

81 citations recorded by the source corpus.

Cholesterol is an essential component of mammalian cell membranes, constituting up to 50% of plasma membrane lipids. By contrast, it accounts for only 5% of lipids in the endoplasmic reticulum (ER)1. The ER enzyme sterol O-acyltransferase 1 (also named acyl-coenzyme A: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 has an essential role in cholesterol homeostasis2,3. ACAT1 has also been implicated in Alzheimer’s disease4, atherosclerosis5 and cancers6. Here we report a cryo-electron microscopy structure of human ACAT1 in complex with nevanimibe7, an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The ACAT1 holoenzyme is a tetramer that consists of two homodimers. Each monomer contains nine transmembrane helices (TMs), six of which (TM4–TM9) form a cavity that accommodates nevanimibe and an endogenous acyl-coenzyme A. This cavity also contains a histidine that has previously been identified as essential for catalytic activity8. Our structural data and biochemical analyses provide a physical model to explain the process of cholesterol esterification, as well as details of the interaction between nevanimibe and ACAT1, which may help to accelerate the development of ACAT1 inhibitors to treat related diseases. The structure of human ACAT1 in complex with the inhibitor nevanimibe is resolved by cryo-electron microscopy.

Subfields: Biochemistry, Molecular Biology, Surgery

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Citations in the corpus

Structure, mechanism, and inhibition of Hedgehog acyltransferase (2021, background): “The majority of MBOATs 16, 2021 Crown Copyright ª 2021 Published by Elsevier Inc. 5025 er the CC BY license (http://creativecommons.org/licenses/by/4.0/). catalyze lipid chain transfer to small-molecule lipid substrates; however, HHAT, alongside porcupine acyltransferase (PORCN) and ghrelin O-acyltr”
Structural model of PORCN illuminates disease-associated variants and drug binding sites (2021, unknown): “The CoA moiety anchors in a pocket on the cytoplasmic face (Figure 3C), similar to how it interacts with ACAT1 (Qian et al., 2020) and DGAT1 (Sui et al., 2020; Wang et al., 2020).”