Crystal structure of the HNF4α ligand binding domain in complex with endogenous fatty acid ligand
Crystal structure of the HNF4α ligand binding domain in complex with endogenous fatty acid ligand
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DOI：
10.1074/jbc.c200420200
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发表时间：
2002-10-11
影响因子：
4.8
通讯作者：
Shoelson, SE
中科院分区：
文献类型：
--
作者：
Dhe-Paganon, S;Duda, K;Shoelson, SE
HNF4 α是核受体家族的孤儿成员，在肝、肠、肾和胰腺β细胞中具有突出的功能。我们已经解决了HNF 4 α配体结合域的X射线晶体结构，它采用了典型的折叠。每个同源二聚体中存在两种构象状态：一种是螺旋12（alpha12）延伸并与alpha10共线的开放形式，另一种是alpha12折叠在结构域主体上的封闭形式。尽管蛋白质在没有添加配体的情况下结晶，但封闭和开放形式的配体结合口袋都含有脂肪酸。脂肪酸离子的羧酸头基在配体结合口袋的一端与Arg（226）的胍基配对，而脂肪族链填充与疏水残基排列的长而窄的通道。这些发现表明，脂肪酸是HNF4 α的内源性配体，并建立了一个框架，了解HNF4 α活性是如何通过配体结合增强和减少MODY1突变。
HNF4alpha is an orphan member of the nuclear receptor family with prominent functions in liver, gut, kidney and pancreatic beta cells. We have solved the x-ray crystal structure of the HNF4alpha ligand binding domain, which adopts a canonical fold. Two conformational states are present within each homodimer: an open form with a helix 12 (alpha12) extended and collinear with alpha10 and a closed form with alpha12 folded against the body of the domain. Although the protein was crystallized without added ligands, the ligand binding pockets of both closed and open forms contain fatty acids. The carboxylic acid headgroup of the fatty acid ion pairs with the guanidinium group of Arg(226) at one end of the ligand binding pocket, while the aliphatic chain fills a long, narrow channel that is lined with hydrophobic residues. These findings suggest that fatty acids are endogenous ligands for HNF4alpha and establish a framework for understanding how HNF4alpha activity is enhanced by ligand binding and diminished by MODY1 mutations.