Structure and mechanism of human diacylglycerol O-acyltransferase 1

Nature. 2020 May;581(7808):329-332. doi: 10.1038/s41586-020-2280-2. Epub 2020 May 13.


Diacylglycerol O-acyltransferase 1 (DGAT1) synthesizes triacylglycerides and is required for dietary fat absorption and fat storage in humans1. DGAT1 belongs to the membrane-bound O-acyltransferase (MBOAT) superfamily, members of which are found in all kingdoms of life and are involved in the acylation of lipids and proteins2,3. How human DGAT1 and other mammalian members of the MBOAT family recognize their substrates and catalyse their reactions is unknown. The absence of three-dimensional structures also hampers rational targeting of DGAT1 for therapeutic purposes. Here we present the cryo-electron microscopy structure of human DGAT1 in complex with an oleoyl-CoA substrate. Each DGAT1 protomer has nine transmembrane helices, eight of which form a conserved structural fold that we name the MBOAT fold. The MBOAT fold in DGAT1 forms a hollow chamber in the membrane that encloses highly conserved catalytic residues. The chamber has separate entrances for each of the two substrates, fatty acyl-CoA and diacylglycerol. DGAT1 can exist as either a homodimer or a homotetramer and the two forms have similar enzymatic activity. The N terminus of DGAT1 interacts with the neighbouring protomer and these interactions are required for enzymatic activity.

Publication types

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

MeSH terms

  • Acyl Coenzyme A / chemistry
  • Acyl Coenzyme A / metabolism
  • Binding Sites
  • Cryoelectron Microscopy*
  • Diacylglycerol O-Acyltransferase / chemistry*
  • Diacylglycerol O-Acyltransferase / genetics
  • Diacylglycerol O-Acyltransferase / metabolism*
  • Diacylglycerol O-Acyltransferase / ultrastructure
  • Diglycerides / metabolism
  • Humans
  • Models, Molecular
  • Protein Multimerization
  • Structure-Activity Relationship
  • Triglycerides / metabolism


  • Acyl Coenzyme A
  • Diglycerides
  • Triglycerides
  • oleoyl-coenzyme A
  • DGAT1 protein, human
  • Diacylglycerol O-Acyltransferase