Gonadotropin-Releasing Hormone (GnRH) Receptor Structure and GnRH Binding.
Gonadotropin-Releasing Hormone (GnRH) Receptor Structure and GnRH Binding.
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DOI：
10.3389/fendo.2017.00274
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发表时间：
2017
影响因子：
5.2
通讯作者：
Manilall A
中科院分区：
文献类型：
--
作者：
Flanagan CA;Manilall A
促性腺激素释放激素(GnRH)调节生殖。人促性腺激素释放激素受体缺乏胞质羧基末端，但具有视紫红质样蛋白偶联受体(GPCRs)的氨基酸序列基序。这篇综述将考虑最近对GPCRs非活性构象和活性构象的X射线晶体结构的描述如何有助于理解GnRH受体的结构、激活机制和配体结合。这些结构证实了配体与不同的细胞外表面结合，而七个跨膜的α-螺旋将激活信号传递到细胞质受体表面，后者结合并激活异源三聚体G蛋白。在A类GPCR结构中，连接不同跨膜(TM)螺旋中拓扑等价残基的40个非共价相互作用是保守的，与激活状态无关。与构象无关的螺旋间接触是一种保守的受体蛋白结构，它们在GnRH受体结构中的重要性受到网络中残基突变的受体表达减少的支持。包括Glu2.53(90)Lys突变在内的许多GnRH受体突变与先天性低促性腺激素低下症有关，涉及构成保守网络的氨基酸。在GPCRs的~250个分子内相互作用中，有一半在非活性结构和活性结构之间存在差异。构象特异的螺旋间接触依赖于激活过程中氨基酸变化的伙伴。保守的非活性构象特异性接触通过稳定TM螺旋3和6以及封闭的G蛋白结合位点的邻近来防止受体激活。参与这些相互作用的GnRH受体残基的突变，如Dry/S基序的Arg3.50(139)或N/DPxxY基序的Tyr7.53(323)，增加或降低受体表达和受体偶联对G蛋白信号的效率，与稳定无效GnRH受体结构的天然残基一致。活跃的构象特异性螺旋间接触稳定了开放的G蛋白结合位点。最近，定义GnRH结合位点的进展放缓，有证据表明Tyr6.58(290)与GnRH的Tyr5接触，而其他残基影响Trp3和Gly10NH2的识别。令人惊讶的一致的观察结果是，破坏GnRH结合的GnRH受体突变对“构象受限的”GnRH多肽的影响较小，现在可以用激动剂结合的多肽受体的晶体结构来解释。对GPCR结构的分析提供了对GnRH受体功能的洞察。
Gonadotropin-releasing hormone (GnRH) regulates reproduction. The human GnRH receptor lacks a cytoplasmic carboxy-terminal tail but has amino acid sequence motifs characteristic of rhodopsin-like, class A, G protein-coupled receptors (GPCRs). This review will consider how recent descriptions of X-ray crystallographic structures of GPCRs in inactive and active conformations may contribute to understanding GnRH receptor structure, mechanism of activation and ligand binding. The structures confirmed that ligands bind to variable extracellular surfaces, whereas the seven membrane-spanning α-helices convey the activation signal to the cytoplasmic receptor surface, which binds and activates heterotrimeric G proteins. Forty non-covalent interactions that bridge topologically equivalent residues in different transmembrane (TM) helices are conserved in class A GPCR structures, regardless of activation state. Conformation-independent interhelical contacts account for a conserved receptor protein structure and their importance in the GnRH receptor structure is supported by decreased expression of receptors with mutations of residues in the network. Many of the GnRH receptor mutations associated with congenital hypogonadotropic hypogonadism, including the Glu2.53(90) Lys mutation, involve amino acids that constitute the conserved network. Half of the ~250 intramolecular interactions in GPCRs differ between inactive and active structures. Conformation-specific interhelical contacts depend on amino acids changing partners during activation. Conserved inactive conformation-specific contacts prevent receptor activation by stabilizing proximity of TM helices 3 and 6 and a closed G protein-binding site. Mutations of GnRH receptor residues involved in these interactions, such as Arg3.50(139) of the DRY/S motif or Tyr7.53(323) of the N/DPxxY motif, increase or decrease receptor expression and efficiency of receptor coupling to G protein signaling, consistent with the native residues stabilizing the inactive GnRH receptor structure. Active conformation-specific interhelical contacts stabilize an open G protein-binding site. Progress in defining the GnRH-binding site has recently slowed, with evidence that Tyr6.58(290) contacts Tyr5 of GnRH, whereas other residues affect recognition of Trp3 and Gly10NH2. The surprisingly consistent observations that GnRH receptor mutations that disrupt GnRH binding have less effect on “conformationally constrained” GnRH peptides may now be explained by crystal structures of agonist-bound peptide receptors. Analysis of GPCR structures provides insight into GnRH receptor function.
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