EMD Serono Research Institute, Billerica, MA 01821, USA.
Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12491-6. doi: 10.1073/pnas.1206643109. Epub 2012 Jul 16.
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 (FSHR(ED)), 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 FSHR(ED). In addition to the known hormone-binding site, FSHR(ED) 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.
FSH 是一种糖蛋白激素，其受体（FSHR）是一种 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（ED）的整个细胞外结构域复合物的晶体结构，包括负责信号特异性的神秘铰链区。令人惊讶的是，与广泛预期的相反，铰链区并没有形成一个单独的结构单元，而是 FSHR（ED）整体结构的一部分。除了已知的激素结合位点外，FSHR（ED）还提供了与激素相互作用的位点：铰链区中的一个磺酪氨酸（sTyr）位点与先前的研究一致，以及一个潜在的变构位点，这可能是由受体三聚化引起的。与其他结构相比，我们的结构表明，FSHR 与配体的相互作用分两步进行：配体募集后识别 sTyr。FSH 首先与 FSHR 的高亲和力激素结合亚结构域结合，并重塑配体构象形成 sTyr 结合口袋。然后，FSHR 将其 sTyr（即，磺化 Tyr335）插入 FSH 新生口袋中，最终导致受体激活。
