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TitleMechanism of action for small-molecule inhibitors of triacylglycerol synthesis.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3100, Year 2023
Publish dateMay 29, 2023
AuthorsXuewu Sui / Kun Wang / Kangkang Song / Chen Xu / Jiunn Song / Chia-Wei Lee / Maofu Liao / Robert V Farese / Tobias C Walther /
PubMed AbstractInhibitors 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 ...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.
External linksNat Commun / PubMed:37248213 / PubMed Central
MethodsEM (single particle)
Resolution3.2 Å
Structure data

28577

8esm

EMDB-28577, PDB-8esm:
Human triacylglycerol synthesizing enzyme DGAT1 in complex with T863 inhibitor
Method: EM (single particle) / Resolution: 3.2 Å

28594

8etm

EMDB-28594, PDB-8etm:
Human triacylglycerol synthesizing enzyme DGAT1 in complex with DGAT1IN1 inhibitor
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-WS0:
{(1r,4r)-4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}acetic acid

ChemComp-WTT:
[(1S,4r)-4-{4-[(4S)-2-({[4-(trifluoromethoxy)phenyl]methyl}carbamoyl)imidazo[1,2-a]pyridin-6-yl]phenyl}cyclohexyl]acetic acid

Source
  • homo sapiens (human)
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / triglyceride biosynthesis / lipid storage / lipid metabolism / membrane protein / TRANSFERASE-TRANSFERASE INHIBITOR complex

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