Sato Takaaki, Kawasaki Takashi, Mine Shouhei, Matsumura Hiroyoshi
Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, 1-8-31 Midorioka, Ikeda, Osaka 563-8577, Japan.
College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan.
Int J Mol Sci. 2016 Nov 18;17(11):1930. doi: 10.3390/ijms17111930.
G protein-coupled receptors (GPCRs) transduce various extracellular signals, such as neurotransmitters, hormones, light, and odorous chemicals, into intracellular signals via G protein activation during neurological, cardiovascular, sensory and reproductive signaling. Common and unique features of interactions between GPCRs and specific G proteins are important for structure-based design of drugs in order to treat GPCR-related diseases. Atomic resolution structures of GPCR complexes with G proteins have revealed shared and extensive interactions between the conserved DRY motif and other residues in transmembrane domains 3 (TM3), 5 and 6, and the target G protein C-terminal region. However, the initial interactions formed between GPCRs and their specific G proteins remain unclear. Alanine scanning mutagenesis of the murine olfactory receptor S6 (OR-S6) indicated that the N-terminal acidic residue of helix 8 of OR-S6 is responsible for initial transient and specific interactions with chimeric Gα, resulting in a response that is 2.2-fold more rapid and 1.7-fold more robust than the interaction with Gα. Our mutagenesis analysis indicates that the hydrophobic core buried between helix 8 and TM1-2 of OR-S6 is important for the activation of both Gα and Gα. This review focuses on the functional role of the C-terminal amphipathic helix 8 based on several recent GPCR studies.
G蛋白偶联受体（GPCRs）在神经、心血管、感觉和生殖信号传导过程中，通过激活G蛋白将各种细胞外信号，如神经递质、激素、光和气味化学物质，转化为细胞内信号。GPCRs与特定G蛋白之间相互作用的共同特征和独特特征，对于基于结构的药物设计以治疗GPCR相关疾病具有重要意义。GPCR与G蛋白复合物的原子分辨率结构揭示了保守的DRY基序与跨膜结构域3（TM3）、5和6中的其他残基以及目标G蛋白C末端区域之间存在共同且广泛的相互作用。然而，GPCRs与其特定G蛋白之间形成的初始相互作用仍不清楚。对小鼠嗅觉受体S6（OR-S6）进行丙氨酸扫描诱变表明，OR-S6第8螺旋的N端酸性残基负责与嵌合Gα的初始瞬时和特异性相互作用，导致的反应比与Gα的相互作用快2.2倍且强度高1.7倍。我们的诱变分析表明，埋在OR-S6第8螺旋和TM1-2之间的疏水核心对于Gα和Gα的激活都很重要。本综述基于最近的几项GPCR研究，重点关注C末端两亲性第8螺旋的功能作用。
