Complement factor C5a is an integral constituent of the complement cascade critically involved in the innate immune response, and it exerts its functions via two distinct receptors, C5aR1 and C5aR2. While C5aR1 is a prototypical G-protein-coupled receptor (GPCR), C5aR2 lacks functional coupling to heterotrimeric G proteins, although both receptors efficiently recruit β arrestins (βarrs). Here, we discuss the recent studies providing direct structural details of ligand–receptor interactions, and a framework of functional bias in this system, including the differences in terms of structural motifs and transducer coupling. We also discuss the functional analogy of C5aR2 with the atypical chemokine receptors (ACKRs), and highlight the future directions to elucidate the mechanistic basis of the functional divergence of these receptors activated by a common natural agonist.

补体因子C5a是关键参与先天免疫反应的补体级联的组成部分，它通过两个不同的受体C5aR1和C5aR2发挥其功能。尽管C5aR1是原型G蛋白偶联受体（GPCR），但C5aR2缺乏与异源三聚G蛋白的功能偶联，尽管这两种受体都能有效地募集β抑制蛋白（βarrs）。在这里，我们讨论了最近的研究，这些研究提供了配体-受体相互作用的直接结构细节，以及该系统中的功能偏差框架，包括结构图案和换能器偶联方面的差异。我们还讨论了C5aR2与非典型趋化因子受体（ACKRs）的功能类比，