Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor

Chengcheng Guan, Yange Niu, Si-Cong Chen, Yunlu Kang, Jing-Xiang Wu, Koji Nishi, Catherine C. Y. Chang, Ta-Yuan Chang, Tuoping Luo and Lei Chen ()
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Chengcheng Guan: Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Yange Niu: Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Si-Cong Chen: Ministry of Education and Beijing National Laboratory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University
Yunlu Kang: Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Jing-Xiang Wu: Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Koji Nishi: Geisel School of Medicine at Dartmouth
Catherine C. Y. Chang: Geisel School of Medicine at Dartmouth
Ta-Yuan Chang: Geisel School of Medicine at Dartmouth
Tuoping Luo: Ministry of Education and Beijing National Laboratory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University
Lei Chen: Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the esterification of cholesterol to generate cholesteryl esters for cholesterol storage. SOAT1 is a target to treat several human diseases. However, its structure and mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The structure of hSOAT1 dimer at 3.5 Å resolution reveals that a small molecule inhibitor CI-976 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, N421 and W420. Our results pave the way for future mechanistic study and rational drug design targeting hSOAT1 and other mammalian MBOAT family members.

Date: 2020
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DOI: 10.1038/s41467-020-16288-4

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