High-affinity agonists reveal recognition motifs for the MRGPRD GPCR

• Published in: Cell reports (Cambridge) 2024-12, Vol.43 (12), p.114942, Article 114942
• Main Authors: Wang, Chunyu, Liu, Yongfeng, Lanier, Marion, Yeager, Adam, Singh, Isha, Gumpper, Ryan H., Krumm, Brian E., DeLeon, Chelsea, Zhang, Shicheng, Boehm, Marcus, Pittner, Richard, Baron, Alain, Dvorak, Lisa, Bacon, Corinne, Shoichet, Brian K., Martinborough, Esther, Fay, Jonathan F., Cao, Can, Roth, Bryan L.
• Format: Article
• Language: English
• Subjects: agonist recognition; CP: Molecular biology; drug discovery; GPCR; MRGPRD; structure
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114942

The human MRGPRD protein is a member of the Mas-related G protein-coupled receptors (MRGPRs) that is involved in the sensing of pain, itch, and other inflammatory stimuli. As with other MRGPRs, MRGPRD is a relatively understudied receptor with few known agonists. The most potent small-molecule agonist of MRGPRD reported so far is β-alanine, with an affinity in the micromole range, which largely restricts its functional study. Here, we report two MRGPRD agonists, EP-2825 and EP-3945, that are approximately 100-fold more potent than β-alanine and determine the structures of MRGPRD-Gq in complex with EP-2825 and EP-3945, respectively. The structures reveal distinct agonist binding modes of MRGPRD and large conformational plasticity of the orthosteric pocket. Collectively, the discovery of high-affinity MRGPRD agonists and their distinct binding modes will facilitate the functional study and the structure-based design of ligands targeting this understudied receptor. [Display omitted] •Two high-affinity MRGPRD agonists, EP-2825 and EP-3945, were discovered•Structures of MRGPRD-Gq complex with ligand EP-2825 and EP3945 were determined•Distinct binding modes of EP-2825 and EP3945 were observed in MRGPRD MRGPRD is an understudied receptor that lacks high-affinity ligands. In this study, Wang et al. reported two high-affinity agonists that are approximately 100-fold more potent than β-alanine for MRGPRD and determined their binding poses at MRGPRD through cryo-EM, which could accelerate the functional study and drug discovery of MRGPRD receptors.