Structure of nevanimibe-bound tetrameric human ACAT1.
Structure of nevanimibe-bound tetrameric human ACAT1.
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DOI：
10.1038/s41586-020-2295-8
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发表时间：
2020-05
期刊：
影响因子：
64.8
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Long T;Sun Y;Hassan A;Qi X;Li X
胆固醇是哺乳动物生理上不可或缺的，如其高达50%的质膜脂质丰度所示;相比之下，内质网（ER）中只有5%的脂质是胆固醇。ER酶固醇O-酰基转移酶1（也称为酰基辅酶A：胆固醇酰基转移酶，ACAT 1）将长链脂肪酸转移至胆固醇，形成胆固醇酯，胆固醇酯聚结成细胞溶质脂滴。在胆固醇过载的条件下，ACAT 1维持ER的低胆固醇浓度，从而在胆固醇稳态中起重要作用。值得注意的是，ACAT 1与阿尔茨海默病、动脉粥样硬化和癌症有关。在这里，我们报告了人类ACAT 1与奈伐米贝复合的冷冻电镜结构，奈伐米贝是一种用于治疗先天性肾上腺增生的临床试验中的抑制剂。全酶是由两个同源二聚体组成的四聚体。每个ACAT 1单体含有9个跨膜螺旋（TM）。在由TM 4-9产生的空腔中观察到Nevanimibe和内源性酰基辅酶A。该空腔含有一个组氨酸，以前显示是催化活性所需的。我们的结构数据沿着生化分析提供了一个物理模型来解释胆固醇酯化的过程。这项工作还提供了nevanimibe和ACAT 1之间的相互作用细节，以加速ACAT 1抑制剂的开发，以治疗相关疾病。
Cholesterol is physiologically indispensable for mammals, as illustrated by its abundance of up to 50% of plasma membrane lipids; in contrast, only 5% of lipids in the endoplasmic reticulum (ER) are cholesterol . The ER enzyme sterol O-acyltransferase 1 (also named acyl-coA: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 plays an essential role in cholesterol homeostasis . Notably, ACAT1 is implicated in Alzheimer’s disease , atherosclerosis , and cancers . Here, we report a cryo-EM structure of human ACAT1 in complex with nevanimibe , an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The holoenzyme is a tetramer made up of two homodimers. Each ACAT1 monomer harbors nine transmembrane helices (TMs). Nevanimibe and an endogenous acyl-CoA are observed in a cavity created by TMs 4–9. The cavity contains a histidine previously shown to be required for catalytic activity. Our structural data along with biochemical analysis provide a physical model to explain the process of cholesterol esterification. This work also provides interaction details between nevanimibe and ACAT1 to accelerate the development of ACAT1 inhibitors to treat related diseases.
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影响因子：
48
作者：
Kucukelbir, Alp;Sigworth, Fred J.;Tagare, Hemant D.
通讯作者：
Tagare, Hemant D.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
Anderson, RA;Joyce, C;Rudel, LL
通讯作者：
Rudel, LL
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
3
作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE