The human formyl peptide receptor 2 (FPR2) plays a crucial role in host defense and inflammation, and has been considered as a drug target for chronic inflammatory diseases. A variety of peptides with different structures and origins have been characterized as FPR2 ligands. However, the ligand-binding modes of FPR2 remain elusive, thereby limiting the development of potential drugs. Here we report the crystal structure of FPR2 bound to the potent peptide agonist WKYMVm at 2.8 Å resolution. The structure adopts an active conformation and exhibits a deep ligand-binding pocket. Combined with mutagenesis, ligand binding and signaling studies, key interactions between the agonist and FPR2 that govern ligand recognition and receptor activation are identified. Furthermore, molecular docking and functional assays reveal key factors that may define binding affinity and agonist potency of formyl peptides. These findings deepen our understanding about ligand recognition and selectivity mechanisms of the formyl peptide receptor family.

人甲酰肽受体2（FPR2）在宿主防御和炎症中起着至关重要的作用，并被认为是慢性炎症性疾病的药物靶标。具有不同结构和起源的多种肽已被表征为FPR2配体。但是，FPR2的配体结合模式仍然难以捉摸，从而限制了潜在药物的开发。在这里，我们报告FPR2的晶体结构以2.8Å的分辨率与有效的肽激动剂WKYMVm结合。该结构采用活性构象，并具有深的配体结合口袋。结合诱变，配体结合和信号传导研究，确定了激动剂和FPR2之间控制配体识别和受体激活的关键相互作用。此外，分子对接和功能测定揭示了可能定义甲酰基肽的结合亲和力和激动剂效力的关键因素。这些发现加深了我们对甲酰基肽受体家族的配体识别和选择性机制的理解。