1. Molecular mechanism of prolactin-releasing peptide recognition and signaling via its G protein-coupled receptor.
- Author
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Li, Yang, Yuan, Qingning, He, Xinheng, Zhang, Yumu, You, Chongzhao, Wu, Canrong, Li, Jingru, Xu, H. Eric, and Zhao, Li-Hua
- Subjects
G protein coupled receptors ,PEPTIDES ,NEUROPEPTIDE Y receptors ,PEPTIDE receptors - Abstract
Prolactin-releasing peptide (PrRP) is an RF-amide neuropeptide that binds and activates its cognate G protein-coupled receptor, prolactin-releasing peptide receptor (PrRPR), also known as GPR10. PrRP and PrRPR are highly conserved across mammals and involved in regulating a range of physiological processes, including stress response, appetite regulation, pain modulation, cardiovascular function, and potentially reproductive functions. Here we present cryo-electron microscopy structures of PrRP-bound PrRPR coupled to G
q or Gi heterotrimer, unveiling distinct molecular determinants underlying the specific recognition of the ligand's C-terminal RF-amide motif. We identify a conserved polar pocket that accommodates the C-terminal amide shared by RF-amide peptides. Structural comparison with neuropeptide Y receptors reveals both similarities and differences in engaging the essential RF/RY-amide motifs. Our findings demonstrate the general mechanism governing RF-amide motif recognition by PrRPR and RF-amide peptide receptors, and provide a foundation for elucidating activation mechanisms and developing selective drugs targeting this important peptide–receptor system. [ABSTRACT FROM AUTHOR]- Published
- 2024
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