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 () and Tobias C. Walther ()
Additional contact information
Xuewu Sui: Harvard T.H. Chan School of Public Health
Kun Wang: Harvard T.H. Chan School of Public Health
Kangkang Song: University of Massachusetts Chan Medical School
Chen Xu: University of Massachusetts Chan Medical School
Jiunn Song: Harvard T.H. Chan School of Public Health
Chia-Wei Lee: Harvard T.H. Chan School of Public Health
Maofu Liao: Harvard Medical School
Robert V. Farese: Harvard T.H. Chan School of Public Health
Tobias C. Walther: Harvard T.H. Chan School of Public Health

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-38934-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38934-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-38934-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().