High-affinity agonists reveal recognition motifs for the MRGPRD GPCR

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.

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Publication Details

Journal
Cell Reports
Published
2024-11-23
DOI
https://doi.org/10.1016/j.celrep.2024.114942
Citations
5
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
1.17

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article

High-affinity agonists reveal recognition motifs for the MRGPRD GPCR

Richard Pittner, Bryan L. Roth, Isha Singh, Brian K. Shoichet et al.
5 citations
Cell Reports
Receptor Mechanisms and Signaling
1.17
article

High-affinity agonists reveal recognition motifs for the MRGPRD GPCR

Richard Pittner, Bryan L. Roth, Isha Singh, Brian K. Shoichet, Can Cao, Esther Martinborough, Ryan H. Gumpper, Adam Yeager, Chunyu Wang, Lisa Dvorak, Chelsea DeLeon, Jonathan F. Fay, Marion Lanier, B. Krumm, Yongfeng Liu, Shicheng Zhang, Corinne Bacon, Marcus F. Boehm, Alain Baron
article en
5 citations

Abstract

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.

Cell ReportsVol. 43(12)
University of North Carolina at Chapel Hill (US), University of California, San Francisco (US), Ligand Pharmaceuticals (United States) (US), University of San Francisco (US)
University of North Carolina, Nvidia, National Institutes of Health
Zero hunger
Openalex Percentile: Top 21%
Receptor Mechanisms and Signaling
1.17
DOIOpen Access PDFOpenAlex
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