Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor
Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor
复制标题
DOI：
10.1073/pnas.1206643109
复制
发表时间：
2012-07-31
影响因子：
11.1
通讯作者：
He, Xiaolin
中科院分区：
文献类型：
--
作者：
Jiang, Xuliang;Liu, Heli;He, Xiaolin
FSH（一种糖蛋白激素）和 FSH 受体（FSHR）（一种 G 蛋白偶联受体）在人类生殖中发挥着核心作用。我们报告了 FSH 与 FSHR (FSHRED) 整个胞外域复合的晶体结构，包括负责信号特异性的神秘铰链区。令人惊讶的是，铰链区并没有像人们普遍预期的那样形成一个单独的结构单元，而是FSHRED整体结构的一部分。除了已知的激素结合位点外，FSHRED 还提供了与激素的相互作用位点：铰链区的磺基酪氨酸 (sTyr) 位点与之前的研究一致，以及假定的受体三聚化产生的潜在外部位点。与其他结构相比，我们的结构表明 FSHR 与其配体相互作用分两个步骤：配体招募，然后是 sTyr 识别。 FSH 首先与 FSHR 的高亲和力激素结合子结构域结合，并重塑配体构象以形成 sTyr 结合袋。然后，FSHR 将其 sTyr（即硫酸化 Tyr335）插入 FSH 新生口袋中，最终导致受体激活。
FSH, a glycoprotein hormone, and the FSH receptor (FSHR), a G protein-coupled receptor, play central roles in human reproduction. We report the crystal structure of FSH in complex with the entire extracellular domain of FSHR (FSHRED), including the enigmatic hinge region that is responsible for signal specificity. Surprisingly, the hinge region does not form a separate structural unit as widely anticipated but is part of the integral structure of FSHRED. In addition to the known hormone-binding site, FSHRED provides interaction sites with the hormone: a sulfotyrosine (sTyr) site in the hinge region consistent with previous studies and a potential exosite resulting from putative receptor trimerization. Our structure, in comparison to others, suggests FSHR interacts with its ligand in two steps: ligand recruitment followed by sTyr recognition. FSH first binds to the high-affinity hormone-binding subdomain of FSHR and reshapes the ligand conformation to form a sTyr-binding pocket. FSHR then inserts its sTyr (i.e., sulfated Tyr335) into the FSH nascent pocket, eventually leading to receptor activation.