دورية أكاديمية
أعرض في EDS

Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis.

التفاصيل البيبلوغرافية
العنوان: Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis.
المؤلفون: Sui X; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.; Department of Biochemistry and Biophysics, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, USA., Wang K; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Song K; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, USA.; Cryo-EM Core Facility, University of Massachusetts Chan Medical School, Worcester, MA, USA., Xu C; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, USA.; Cryo-EM Core Facility, University of Massachusetts Chan Medical School, Worcester, MA, USA., Song J; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Lee CW; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Liao M; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. liaomf@sustech.edu.cn.; School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. liaomf@sustech.edu.cn., Farese RV Jr; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA. robert@mskcc.org.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. robert@mskcc.org.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. robert@mskcc.org.; Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. robert@mskcc.org., Walther TC; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA. twalther@mskcc.org.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. twalther@mskcc.org.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. twalther@mskcc.org.; Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. twalther@mskcc.org.; Howard Hughes Medical Institute, Boston, MA, USA. twalther@mskcc.org.
المصدر: Nature communications [Nat Commun] 2023 May 29; Vol. 14 (1), pp. 3100. Date of Electronic Publication: 2023 May 29.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Acyltransferases*/metabolism , Diacylglycerol O-Acyltransferase*/genetics , Diacylglycerol O-Acyltransferase*/metabolism, Lipogenesis ; Sterol O-Acyltransferase/chemistry ; Triglycerides
مستخلص: 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.
(© 2023. The Author(s).)
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معلومات مُعتمدة: P30 CA008748 United States CA NCI NIH HHS; R01 GM124348 United States GM NIGMS NIH HHS; United States HHMI Howard Hughes Medical Institute
المشرفين على المادة: EC 2.3.- (Acyltransferases)
EC 2.3.1.20 (Diacylglycerol O-Acyltransferase)
EC 2.3.1.26 (Sterol O-Acyltransferase)
0 (Triglycerides)
تواريخ الأحداث: Date Created: 20230529 Date Completed: 20230531 Latest Revision: 20240607
رمز التحديث: 20240607
مُعرف محوري في PubMed: PMC10227072
DOI: 10.1038/s41467-023-38934-3
PMID: 37248213
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-023-38934-3