8ESM

Human triacylglycerol synthesizing enzyme DGAT1 in complex with T863 inhibitor

Summary for 8ESM

• Entry DOI: 10.2210/pdb8esm/pdb
• EMDB information: 28577
• Descriptor: Diacylglycerol O-acyltransferase 1, {(1r,4r)-4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}acetic acid (2 entities in total)
• Functional Keywords: triglyceride biosynthesis, lipid storage, lipid metabolism, membrane protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 111467.20

Authors

Sui, X.,Kun, W.,Walther, T.,Farese, R.,Liao, M. (deposition date: 2022-10-14, release date: 2023-06-07, Last modification date: 2025-05-21)

Primary citation

Sui, X.,Wang, K.,Song, K.,Xu, C.,Song, J.,Lee, C.W.,Liao, M.,Farese Jr., R.V.,Walther, T.C.
Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis.
Nat Commun, 14:3100-3100, 2023

PubMed 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.

PubMed: 37248213
DOI: 10.1038/s41467-023-38934-3

Experimental method

ELECTRON MICROSCOPY (3.2 Å)