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dc.contributor.authorSui, Xuewu
dc.contributor.authorWang, Kun
dc.contributor.authorGluchowski, Nina
dc.contributor.authorElliott, Shane
dc.contributor.authorLiao, Maofu
dc.contributor.authorWalther, Tobias
dc.contributor.authorFarese, Robert
dc.date.accessioned2022-06-02T16:39:11Z
dc.date.issued2020-05-13
dc.identifier.citationSui, Xuewu, Wang, Kun, Gluchowski, Nina L, Elliott, Shane D, Liao, Maofu, Walther, Tobias C, and Farese, Jr, Robert V. "Structure and Catalytic Mechanism of a Human Triacylglycerol-synthesis Enzyme." Nature (London) 581, no. 7808 (2020): 323-28.en_US
dc.identifier.issn0028-0836en_US
dc.identifier.issn1476-4687en_US
dc.identifier.urihttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37371854*
dc.description.abstractTriglycerides (triacylglycerols, TGs) store metabolic energy in organisms and have industrial uses for foods and fuels. Excessive accumulation of TGs in humans causes obesity and is associated with metabolic diseases1. TG synthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes2-4 whose structures and catalytic mechanisms are 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 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 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 center 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 an acyl-acceptor molecule, is located within the reaction center, orthogonal to acyl-CoA. Insights provided by the DGAT1 structures, together with mutagenesis and functional studies, give rise to a model of catalysis for DGAT’s generation of TGs.en_US
dc.language.isoen_USen_US
dc.publisherSpringer Science and Business Media LLCen_US
dc.relationNatureen_US
dash.licenseMETA_ONLY
dc.subjectMultidisciplinaryen_US
dc.titleStructure and Catalytic Mechanism of a Human Triacylglycerol-synthesis Enzymeen_US
dc.typeJournal Articleen_US
dc.description.versionAccepted Manuscripten_US
dc.relation.journalNature (London)en_US
dash.waiver2020-03-10
dc.date.available2022-06-02T16:39:11Z
dash.affiliation.otherHarvard T.H. Chan School of Public Healthen_US
dc.identifier.doi10.1038/s41586-020-2289-6
dc.source.journalNature
dash.waiver.reasonNature requires this for publication.en_US
dash.source.volume581;7808en_US
dash.source.page323-328en_US
dash.contributor.affiliatedSui, Xuewu
dash.contributor.affiliatedWang, Kun
dash.contributor.affiliatedElliott, Shane
dash.contributor.affiliatedWalther, Tobias
dash.contributor.affiliatedFarese, Robert
dash.contributor.affiliatedGluchowski, Nina
dash.contributor.affiliatedLiao, Maofu


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