High-affinity agonists reveal recognition motifs for the MRGPRD GPCR
Chunyu Wang,
Yongfeng Liu,
Marion Lanier,
Adam Yeager,
Isha Singh,
Ryan H. Gumpper,
Brian E. Krumm,
Chelsea DeLeon,
Shicheng Zhang,
Marcus Boehm,
Richard Pittner,
Alain Baron,
Lisa Dvorak,
Corinne Bacon,
Brian K. Shoichet,
Esther Martinborough,
Jonathan F. Fay,
Can Cao,
Bryan L. Roth
Affiliations
Chunyu Wang
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
Yongfeng Liu
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
Marion Lanier
Escient Pharmaceuticals, 10578 Science Center Drive, Suite 250, San Diego, CA 92121, USA
Adam Yeager
Escient Pharmaceuticals, 10578 Science Center Drive, Suite 250, San Diego, CA 92121, USA
Isha Singh
Department of Pharmaceutical Sciences, University of California, San Francisco, School of Medicine, San Francisco, CA, USA
Ryan H. Gumpper
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
Brian E. Krumm
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
Chelsea DeLeon
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
Shicheng Zhang
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
Marcus Boehm
Escient Pharmaceuticals, 10578 Science Center Drive, Suite 250, San Diego, CA 92121, USA
Richard Pittner
Escient Pharmaceuticals, 10578 Science Center Drive, Suite 250, San Diego, CA 92121, USA
Alain Baron
Escient Pharmaceuticals, 10578 Science Center Drive, Suite 250, San Diego, CA 92121, USA
Lisa Dvorak
Escient Pharmaceuticals, 10578 Science Center Drive, Suite 250, San Diego, CA 92121, USA
Corinne Bacon
Escient Pharmaceuticals, 10578 Science Center Drive, Suite 250, San Diego, CA 92121, USA
Brian K. Shoichet
Department of Pharmaceutical Sciences, University of California, San Francisco, School of Medicine, San Francisco, CA, USA
Esther Martinborough
Escient Pharmaceuticals, 10578 Science Center Drive, Suite 250, San Diego, CA 92121, USA; Corresponding author
Jonathan F. Fay
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; Corresponding author
Can Cao
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; Corresponding author
Bryan L. Roth
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; Corresponding Author
Summary: 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.
