2. Academic Validation
  3. High-affinity agonists reveal recognition motifs for the MRGPRD GPCR

High-affinity agonists reveal recognition motifs for the MRGPRD GPCR

  • Cell Rep. 2024 Dec 24;43(12):114942. doi: 10.1016/j.celrep.2024.114942.
Chunyu Wang 1,  Yongfeng Liu 2,  Marion Lanier 3,  Adam Yeager 3,  Isha Singh 4,  Ryan H Gumpper 5,  Brian E Krumm 6,  Chelsea DeLeon 6,  Shicheng Zhang 6,  Marcus Boehm 3,  Richard Pittner 3,  Alain Baron 3,  Lisa Dvorak 3,  Corinne Bacon 3,  Brian K Shoichet 4,  Esther Martinborough 7,  Jonathan F Fay 8,  Can Cao 9,  Bryan L Roth 10
Affiliations

Affiliations

  • 1 Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.
  • 2 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA; National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 3 Escient Pharmaceuticals, 10578 Science Center Drive, Suite 250, San Diego, CA 92121, USA.
  • 4 Department of Pharmaceutical Sciences, University of California, San Francisco, School of Medicine, San Francisco, CA, USA.
  • 5 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, USA.
  • 6 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 7 Escient Pharmaceuticals, 10578 Science Center Drive, Suite 250, San Diego, CA 92121, USA. Electronic address: emartinborough@escientpharma.com.
  • 8 Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: jfay@som.umaryland.edu.
  • 9 Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China. Electronic address: caocan23@ustc.edu.cn.
  • 10 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA; National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Division of Chemical Biology and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Electronic address: bryan_roth@med.unc.edu.
PMID: 39580805 DOI: 10.1016/j.celrep.2024.114942
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.

Keywords

CP: Molecular biology; GPCR; MRGPRD; agonist recognition; drug discovery; structure.

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