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CryoEM structure of Gq-coupled MRGPRD with a new agonist EP-2825
Structural highlights
FunctionMRGRD_HUMAN May regulate nociceptor function and/or development, including the sensation or modulation of pain. Functions as a specific membrane receptor for beta-alanine. Beta-alanine at micromolar doses specifically evoked Ca(2+) influx in cells expressing the receptor. Beta-alanine decreases forskolin-stimulated cAMP production in cells expressing the receptor, suggesting that the receptor couples with G-protein G(q) and G(i). Publication Abstract from PubMedThe 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 beta-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 beta-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. High-affinity agonists reveal recognition motifs for the MRGPRD GPCR.,Wang C, Liu Y, Lanier M, Yeager A, Singh I, Gumpper RH, Krumm BE, DeLeon C, Zhang S, Boehm M, Pittner R, Baron A, Dvorak L, Bacon C, Shoichet BK, Martinborough E, Fay JF, Cao C, Roth BL Cell Rep. 2024 Nov 23;43(12):114942. doi: 10.1016/j.celrep.2024.114942. PMID:39580805[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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