气候变化领域集成服务门户(CCPortal): Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms

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DOI	10.1073/pnas.2024149118
	Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms
	Xiao X.; Kim Y.; Romartinez-Alonso B.; Sirvydis K.; Ory D.S.; Schwabe J.W.R.; Jung M.E.; Tontonoz P.
发表日期	2021
ISSN	00278424
卷号	118 期号:2
英文摘要	The Aster proteins (encoded by the Gramd1a-c genes) contain a ligand-binding fold structurally similar to a START domain and mediate nonvesicular plasma membrane (PM) to endoplasmic reticulum (ER) cholesterol transport. In an effort to develop small molecule modulators of Asters, we identified 20α-hydroxycholesterol (HC) and U18666A as lead compounds. Unfortunately, both 20α-HC and U18666A target other sterol homeostatic proteins, limiting their utility. 20α-HC inhibits sterol regulatory element-binding protein 2 (SREBP2) processing, and U18666A is an inhibitor of the vesicular trafficking protein Niemann-Pick C1 (NPC1). To develop potent and selective Aster inhibitors, we synthesized a series of compounds by modifying 20α-HC and U18666A. Among these, AI (Aster inhibitor)1l, which has a longer side chain than 20α-HC, selectively bound to Aster-C. The crystal structure of Aster-C in complex with AI-1l suggests that sequence and flexibility differences in the loop that gates the binding cavity may account for the ligand specificity for Aster C. We further identified the U18666A analog AI-3d as a potent inhibitor of all three Aster proteins. AI-3d blocks the ability of Asters to bind and transfer cholesterol in vitro and in cells. Importantly, AI-3d also inhibits the movement of low-density lipoprotein (LDL) cholesterol to the ER, although AI-3d does not block NPC1. This finding positions the nonvesicular Aster pathway downstream of NPC1-dependent vesicular transport in the movement of LDL cholesterol to the ER. Selective Aster inhibitors represent useful chemical tools to distinguish vesicular and nonvesicular sterol transport mechanisms in mammalian cells. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cholesterol; Lipid metabolism; Lipid transport
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181034
作者单位	Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, United States; Department of Biological Chemistry, University of California, Los Angeles, CA 90095, United States; Department of Chemistry, University of California, Los Angeles, CA 90095, United States; Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, LE1 7RH, United Kingdom; Department of Medicine, Washington University, School of Medicine, St. Louis, MO 63110, United States
推荐引用方式 GB/T 7714	Xiao X.,Kim Y.,Romartinez-Alonso B.,et al. Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms[J],2021,118(2).
APA	Xiao X..,Kim Y..,Romartinez-Alonso B..,Sirvydis K..,Ory D.S..,...&Tontonoz P..(2021).Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms.Proceedings of the National Academy of Sciences of the United States of America,118(2).
MLA	Xiao X.,et al."Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms".Proceedings of the National Academy of Sciences of the United States of America 118.2(2021).