Structure of nevanimibe-bound tetrameric human ACAT1

doi:10.1038/s41586-020-2295-8

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2295-8
	Structure of nevanimibe-bound tetrameric human ACAT1
	Ma, Xiyu 1,2; Claus, Lucas A. N.3,4; Leslie, Michelle E.5,11; Tao, Kai 6,7; Wu, Zhiping 8,9; Liu, Jun 1,2; Yu, Xiao 2; Li, Bo 2,10; Zhou, Jinggeng 1,2; Savatin, Daniel V.3,4; Peng, Junmin 8,9; Tyler, Brett M.6,7; Heese, Antje 5; Russinova, Eugenia 3,4; He, Ping 1,2; Shan, Libo 2,10
	2020-05-01
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	581 期号:7808 页码:339-U214
文章类型	Article
语种	英语
国家	USA
英文关键词	The structure of human ACAT1 in complex with the inhibitor nevanimibe is resolved by cryo-electron microscopy. Cholesterol is an essential component of mammalian cell membranes, constituting up to 50% of plasma membrane lipids. By contrast, it accounts for only 5% of lipids in the endoplasmic reticulum (ER)(1). The ER enzyme sterol O-acyltransferase 1 (also named acyl-coenzyme A:cholesterol acyltransferase, ACAT1) transfers a long-chain fatty acid to cholesterol to form cholesteryl esters that coalesce into cytosolic lipid droplets. Under conditions of cholesterol overload, ACAT1 maintains the low cholesterol concentration of the ER and thereby has an essential role in cholesterol homeostasis(2,3). ACAT1 has also been implicated in Alzheimer' s disease(4), atherosclerosis(5) and cancers(6). Here we report a cryo-electron microscopy structure of human ACAT1 in complex with nevanimibe(7), an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The ACAT1 holoenzyme is a tetramer that consists of two homodimers. Each monomer contains nine transmembrane helices (TMs), six of which (TM4-TM9) form a cavity that accommodates nevanimibe and an endogenous acyl-coenzyme A. This cavity also contains a histidine that has previously been identified as essential for catalytic activity(8). Our structural data and biochemical analyses provide a physical model to explain the process of cholesterol esterification, as well as details of the interaction between nevanimibe and ACAT1, which may help to accelerate the development of ACAT1 inhibitors to treat related diseases.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000532688300009
WOS关键词	COA-CHOLESTEROL ACYLTRANSFERASE ; ACYL-COENZYME ; O-ACYLTRANSFERASES ; IDENTIFICATION ; EXPRESSION ; INHIBITOR ; CLONING ; DOMAIN ; CELLS ; MODEL
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计	被引频次：49[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281035
专题	地球科学资源环境科学气候变化
作者单位	1.Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA; 2.Texas A&M Univ, Inst Plant Genom & Biotechnol, College Stn, TX 77843 USA; 3.Univ Ghent, Dept Plant Biotechnol & Bioinformat, Ghent, Belgium; 4.VIB, Ctr Plant Syst Biol, Ghent, Belgium; 5.Univ Missouri, Dept Biochem, Interdisciplinary Plant Grp, Columbia, MO USA; 6.Oregon State Univ, Ctr Genome Res & Biocomp, Corvallis, OR 97331 USA; 7.Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA; 8.St Jude Childrens Res Hosp, Ctr Prote & Metabol, Dept Struct Biol, 332 N Lauderdale St, Memphis, TN 38105 USA; 9.St Jude Childrens Res Hosp, Ctr Prote & Metabol, Dept Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA; 10.Texas A&M Univ, Dept Plant Pathol & Microbiol, College Stn, TX 77843 USA; 11.Elemental Enzymes, St Louis, MO USA
推荐引用方式 GB/T 7714	Ma, Xiyu,Claus, Lucas A. N.,Leslie, Michelle E.,et al. Structure of nevanimibe-bound tetrameric human ACAT1[J]. NATURE,2020,581(7808):339-U214.
APA	Ma, Xiyu.,Claus, Lucas A. N..,Leslie, Michelle E..,Tao, Kai.,Wu, Zhiping.,...&Shan, Libo.(2020).Structure of nevanimibe-bound tetrameric human ACAT1.NATURE,581(7808),339-U214.
MLA	Ma, Xiyu,et al."Structure of nevanimibe-bound tetrameric human ACAT1".NATURE 581.7808(2020):339-U214.