6VZ1

Cryo-EM structure of human diacylglycerol O-acyltransferase 1 complexed with acyl-CoA substrate

Summary for 6VZ1

• Entry DOI: 10.2210/pdb6vz1/pdb
• EMDB information: 21481
• Descriptor: Diacylglycerol O-acyltransferase 1, [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate, S-{(3R,5R,9R)-1-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydrofuran-2-yl]-3,5,9-trihydroxy-8,8-dimethyl-3,5-dioxido-10,14-dioxo-2,4,6-trioxa-11,15-diaza-3lambda~5~,5lambda~5~-diphosphaheptadecan-17-yl} (9Z)-octadec-9-enethioate (non-preferred name) (3 entities in total)
• Functional Keywords: triglyceride biosynthesis, lipid storage, lipid metabolism, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 115614.21

Authors

Sui, X.,Wang, K.,Gluchowski, N.,Liao, M.,Walther, C.T.,Farese Jr., V.R. (deposition date: 2020-02-27, release date: 2020-05-13, Last modification date: 2025-05-14)

Primary citation

Sui, X.,Wang, K.,Gluchowski, N.L.,Elliott, S.D.,Liao, M.,Walther, T.C.,Farese Jr., R.V.
Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme.
Nature, 581:323-328, 2020

PubMed Abstract: Triacylglycerols store metabolic energy in organisms and have industrial uses as foods and fuels. Excessive accumulation of triacylglycerols in humans causes obesity and is associated with metabolic diseases. Triacylglycerol synthesis is catalysed by acyl-CoA diacylglycerol acyltransferase (DGAT) enzymes, the structures and catalytic mechanisms of which remain unknown. Here we determined the structure of dimeric human DGAT1, a member of the membrane-bound O-acyltransferase (MBOAT) family, by cryo-electron microscopy at approximately 3.0 Å resolution. DGAT1 forms a homodimer through N-terminal segments and a hydrophobic interface, with putative active sites within the membrane region. A structure obtained with oleoyl-CoA substrate resolved at approximately 3.2 Å shows that the CoA moiety binds DGAT1 on the cytosolic side and the acyl group lies deep within a hydrophobic channel, positioning the acyl-CoA thioester bond near an invariant catalytic histidine residue. The reaction centre is located inside a large cavity, which opens laterally to the membrane bilayer, providing lipid access to the active site. A lipid-like density-possibly representing an acyl-acceptor molecule-is located within the reaction centre, orthogonal to acyl-CoA. Insights provided by the DGAT1 structures, together with mutagenesis and functional studies, provide the basis for a model of the catalysis of triacylglycerol synthesis by DGAT.

PubMed: 32433611
DOI: 10.1038/s41586-020-2289-6

Experimental method

ELECTRON MICROSCOPY (3.2 Å)