The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, Gannan Medical University, Ganzhou 341000, China; Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China.
J Struct Biol. 2024 Sep;216(3):108117. doi: 10.1016/j.jsb.2024.108117. Epub 2024 Aug 15.
The complement system is a complex network of proteins that plays a crucial role in the innate immune response. One important component of this system is the C5a-C5aR1 complex, which is critical in the recruitment and activation of immune cells. In-depth investigation of the activation mechanism as well as biased signaling of the C5a-C5aR1 system will facilitate the elucidation of C5a-mediated pathophysiology. In this study, we determined the structure of C5a-C5aR1-Gi complex at a high resolution of 3 Å using cryo-electron microscopy (Cryo-EM). Our results revealed the binding site of C5a, which consists of a polar recognition region on the extracellular side and an amphipathic pocket within the transmembrane domain. Furthermore, we found that C5a binding induces conformational changes of C5aR1, which subsequently leads to the activation of G protein signaling pathways. Notably, a key residue (M265) located on transmembrane helix 6 (TM6) was identified to play a crucial role in regulating the recruitment of β-arrestin driven by C5a. This study provides more information about the structure and function of the human C5a-C5aR1 complex, which is essential for the proper functioning of the complement system. The findings of this study can also provide a foundation for the design of new pharmaceuticals targeting this receptor with bias or specificity.
补体系统是一个由蛋白质组成的复杂网络，在先天免疫反应中起着至关重要的作用。该系统的一个重要组成部分是 C5a-C5aR1 复合物，它在招募和激活免疫细胞方面至关重要。深入研究 C5a-C5aR1 系统的激活机制和偏向信号转导将有助于阐明 C5a 介导的病理生理学。在这项研究中，我们使用冷冻电镜（Cryo-EM）以 3Å 的高分辨率确定了 C5a-C5aR1-Gi 复合物的结构。我们的结果揭示了 C5a 的结合位点，它由细胞外的极性识别区域和跨膜域内的两亲口袋组成。此外，我们发现 C5a 结合诱导 C5aR1 的构象变化，随后导致 G 蛋白信号通路的激活。值得注意的是，鉴定出位于跨膜螺旋 6（TM6）上的关键残基（M265）在调节 C5a 驱动的β-arrestin 募集中起着关键作用。这项研究提供了更多关于人 C5a-C5aR1 复合物的结构和功能的信息，这对于补体系统的正常功能至关重要。这项研究的发现还可以为设计针对该受体的具有偏向性或特异性的新型药物提供基础。
