Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis

Xuewu Sui; Kun Wang; Kangkang Song; Chen Xu; Jiunn Song; Chia-Wei Lee; Maofu Liao; Robert V Farese Jr; Tobias C Walther

doi:10.1038/s41467-023-38934-3

Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis

Nat Commun. 2023 May 29;14(1):3100. doi: 10.1038/s41467-023-38934-3.

Authors

Xuewu Sui^{1

2

3}, Kun Wang^{1

2}, Kangkang Song^{4

5}, Chen Xu^{4

5}, Jiunn Song^{1

2}, Chia-Wei Lee^{1

2}, Maofu Liao^#^{6

7}, Robert V Farese Jr^#^{8

9

10

11}, Tobias C Walther^#^{12

13

14

15

16}

Affiliations

¹ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
² Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
³ Department of Biochemistry and Biophysics, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, USA.
⁴ Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁵ Cryo-EM Core Facility, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁶ Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
⁷ School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. [email protected].
⁸ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA. [email protected].
⁹ Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
¹¹ Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
¹² Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA. [email protected].
¹³ Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
¹⁵ Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
¹⁶ Howard Hughes Medical Institute, Boston, MA, USA. [email protected].

^# Contributed equally.

Abstract

Inhibitors of triacylglycerol (TG) synthesis have been developed to treat metabolism-related diseases, but we know little about their mechanisms of action. Here, we report cryo-EM structures of the TG-synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a membrane bound O-acyltransferase (MBOAT), in complex with two different inhibitors, T863 and DGAT1IN1. Each inhibitor binds DGAT1's fatty acyl-CoA substrate binding tunnel that opens to the cytoplasmic side of the ER. T863 blocks access to the tunnel entrance, whereas DGAT1IN1 extends further into the enzyme, with an amide group interacting with more deeply buried catalytic residues. A survey of DGAT1 inhibitors revealed that this amide group may serve as a common pharmacophore for inhibition of MBOATs. The inhibitors were minimally active against the related MBOAT acyl-CoA:cholesterol acyltransferase 1 (ACAT1), yet a single-residue mutation sensitized ACAT1 for inhibition. Collectively, our studies provide a structural foundation for developing DGAT1 and other MBOAT inhibitors.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Acyltransferases* / metabolism
Diacylglycerol O-Acyltransferase* / genetics
Diacylglycerol O-Acyltransferase* / metabolism
Lipogenesis
Sterol O-Acyltransferase / chemistry
Triglycerides

Substances

Acyltransferases
Diacylglycerol O-Acyltransferase
Sterol O-Acyltransferase
Triglycerides

Abstract

Publication types

MeSH terms

Substances

Grants and funding