6L47

Structure of the human sterol O-acyltransferase 1 in complex with CI-976

Summary for 6L47

• Entry DOI: 10.2210/pdb6l47/pdb
• EMDB information: 0831
• Descriptor: Sterol O-acyltransferase 1, 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide, CHOLESTEROL (3 entities in total)
• Functional Keywords: soat, acat, mboat, membrane protein, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 116149.98

Authors

Chen, L.,Guan, C.,Niu, Y. (deposition date: 2019-10-16, release date: 2020-04-29, Last modification date: 2024-10-16)

Primary citation

Guan, C.,Niu, Y.,Chen, S.C.,Kang, Y.,Wu, J.X.,Nishi, K.,Chang, C.C.Y.,Chang, T.Y.,Luo, T.,Chen, L.
Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor.
Nat Commun, 11:2478-2478, 2020

PubMed 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.

PubMed: 32424158
DOI: 10.1038/s41467-020-16288-4

Experimental method

ELECTRON MICROSCOPY (3.5 Å)