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Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor.

<div class='caption-title'>The enzymatic reaction catalyzed by hSOAT1.</div>
<div class='caption-title'>Cryo-EM maps of the human SOAT1 tetramer.</div>
<div class='caption-title'>The structure of hSOAT1 dimer.</div>
Guan C, Niu Y, Chen SC, Kang Y, Wu JX, Nishi K, Chang CCY, Chang TY, Luo T, Chen L
OpenAccess logo Nat Commun 11 2478 (2020)
Cited: 36 times
EuropePMC logo PMID: 32424158

Abstract

Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the esterification of cholesterol to generate cholesteryl esters for cholesterol storage. SOAT1 is a target to treat several human diseases. However, its structure and mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The structure of hSOAT1 dimer at 3.5 Å resolution reveals that a small molecule inhibitor CI-976 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, N421 and W420. Our results pave the way for future mechanistic study and rational drug design targeting hSOAT1 and other mammalian MBOAT family members.

Reviews - 6l48 mentioned but not cited (2)

  1. Ghrelin octanoylation by ghrelin O-acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling. Davis TR, Pierce MR, Novak SX, Hougland JL. Open Biol 11 210080 (2021)
  2. A rising tide lifts all MBOATs: recent progress in structural and functional understanding of membrane bound O-acyltransferases. Pierce MR, Hougland JL. Front Physiol 14 1167873 (2023)


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  2. The structural basis for the phospholipid remodeling by lysophosphatidylcholine acyltransferase 3. Zhang Q, Yao D, Rao B, Jian L, Chen Y, Hu K, Xia Y, Li S, Shen Y, Qin A, Zhao J, Zhou L, Lei M, Jiang XC, Cao Y. Nat Commun 12 6869 (2021)
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  4. Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate. Hu A, Zhang JZ, Wang J, Li CC, Yuan M, Deng G, Lin ZC, Qiu ZP, Liu HY, Wang XW, Wei PC, He X, Zhao X, Qiu WW, Song BL. Cell Res 32 288-301 (2022)
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  7. High-affinity SOAT1 ligands remodeled cholesterol metabolism program to inhibit tumor growth. Wang Z, Wang M, Zhang M, Xu K, Zhang X, Xie Y, Zhang Y, Chang C, Li X, Sun A, He F. BMC Med 20 292 (2022)
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  9. Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity. Harned TC, Stan RV, Cao Z, Chakrabarti R, Higgs HN, Chang CCY, Chang TY. Int J Mol Sci 24 5525 (2023)
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  11. New Terpendole Congeners, Inhibitors of Sterol O-Acyltransferase, Produced by Volutella citrinella BF-0440. Nur EAA, Kobayashi K, Amagai A, Ohshiro T, Tomoda H. Molecules 25 E3079 (2020)
  12. Combined Lipidomics and Network Pharmacology Study of Protective Effects of Salvia miltiorrhiza against Blood Stasis Syndrome. Jin Y, Xie Z, Li S, Zeng X, Wang L, Hu P, Zhang H, Xiao X. Evid Based Complement Alternat Med 2021 5526778 (2021)
  13. Nanodisc scaffold peptide (NSPr) replaces detergent by reconstituting acyl-CoA:cholesterol acyltransferase 1 into peptidiscs. Neumann B, Chao K, Chang CCY, Chang TY. Arch Biochem Biophys 691 108518 (2020)
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  15. The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification. Wang K, Lee CW, Sui X, Kim S, Wang S, Higgs AB, Baublis AJ, Voth GA, Liao M, Walther TC, Farese RV. Nat Commun 14 3533 (2023)
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  19. Cellular Uptake of a Fluorescent Ligand Reveals Ghrelin O-Acyltransferase Interacts with Extracellular Peptides and Exhibits Unexpected Localization for a Secretory Pathway Enzyme. Campaña MB, Davis TR, Novak SX, Cleverdon ER, Bates M, Krishnan N, Curtis ER, Childs MD, Pierce MR, Morales-Rodriguez Y, Sieburg MA, Hehnly H, Luyt LG, Hougland JL. ACS Chem Biol 18 1880-1890 (2023)
  20. Combined Computational-Biochemical Approach Offers an Accelerated Path to Membrane Protein Solubilization. Pierce MR, Ji J, Novak SX, Sieburg MA, Nangia S, Nangia S, Hougland JL. J Chem Inf Model 63 7159-7170 (2023)
  21. DNA methyltransferase 1 deficiency improves macrophage motility and wound healing by ameliorating cholesterol accumulation. Zhao C, Yang Q, Tang R, Li W, Wang J, Yang F, Zhao J, Zhu J, Pang W, Li N, Zhang X, Tian XY, Yao W, Zhou J. NPJ Regen Med 8 29 (2023)
  22. Mechanism of D-alanine transfer to teichoic acids shows how bacteria acylate cell envelope polymers. Schultz BJ, Snow ED, Walker S. Nat Microbiol 8 1318-1329 (2023)
  23. Reversible translocation of acyl-CoA:cholesterol acyltransferase (ACAT) between the endoplasmic reticulum and vesicular structures. Schiffmann A, Ahlswede L, Gimpl G. Front Mol Biosci 10 1258799 (2023)
  24. Structure of human phagocyte NADPH oxidase in the activated state. Liu X, Shi Y, Liu R, Song K, Chen L. Nature 627 189-195 (2024)


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