EMD-47114
CryoEM structure of Gq-coupled MRGPRD with a new agonist EP-3945
EMD-47114
Single-particle2.9 Å
Deposition: 24/09/2024Map released: 11/12/2024
Last modified: 11/12/2024
Sample Organism:
Homo sapiens,
Mus musculus
Sample: EP-3945-bound MRGPRD-Gq complex
Fitted models: 9dqj (Avg. Q-score: 0.095)
Deposition Authors: Cao C, Wang C, Liu Y, Fay JF, Roth BL
Sample: EP-3945-bound MRGPRD-Gq complex
Fitted models: 9dqj (Avg. Q-score: 0.095)
Deposition Authors: Cao C, Wang C, Liu Y, Fay JF, Roth BL
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
(2024) Cell Rep , 43 , 114942 - 114942
(2024) Cell Rep , 43 , 114942 - 114942
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.
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.