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Review
. 2023 Apr;44(4):237-251.
doi: 10.1016/j.tips.2023.02.002. Epub 2023 Mar 2.

The structure, function, and pharmacology of MRGPRs

Can Cao  1 , Bryan L Roth  2
Affiliations
Review

The structure, function, and pharmacology of MRGPRs

Can Cao et al. Trends Pharmacol Sci. 2023 Apr.

Abstract

Mas-related G protein-coupled receptor (MRGPR) family members play important roles in the sensation of noxious stimuli and represent novel targets for the treatment of itch and pain. MRGPRs recognize a diversity of agonists and display complicated downstream signaling profiles, high sequence diversity across species, and many polymorphisms in humans. The recent structural advances on MRGPRs reveal unique structural features and diverse agonist recognition modes of this receptor family, which should facilitate the structure-based drug discovery at MRGPRs. In addition, the newly discovered ligands also provide valuable tools to explore the function and the therapeutic potential of MRGPRs. In this review, we discuss these progresses in our understanding of MRGPRs and highlight the challenges and potential opportunities for the future drug discovery at these receptors.

Keywords: MRGPRs; drug discovery; function; ligand recognition; polymorphism; structure.

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Conflict of interest statement

Declaration of interests B.L.R. and C.C. are listed as inventors on a patent application related to MRGPRX2 antagonists.

Figures

Figure 1.
Figure 1.. Human MRGPRs in the sensation of itch and pain.
Key agonists that have been reported to elicit itch or pain signals are shown. Figure created with Biorender.com.
Figure 2.
Figure 2.. G protein signaling of MRGPRs.
(A) MRGPRX2 couple to all the G protein subfamilies in the in vitro G protein dissociation assay. The activation of Gi and Gq by MRGPRX2 are stronger than Gs and G12/13. Figure created with Biorender.com. (B) Sequence alignment generated by GPCRDB [81] shows that MRGPRE, MRGPRF and MRGPRG have distinct ICL2 residue composition, especially the residue 34.51, compared with other MRGPRs. (C) Structural comparison of human MRGPRE AlphaFold model with MRGPRX2-Gq complex (PDB: 7S8N), showing that A34.51 in MRGPRE may weaken the interactions between the receptor and Gq.
Figure 3.
Figure 3.. Sequence diversity of MRGPRs.
(A) Sequence alignment between human MRGPRX4 and rhesus macaque MRGPRX4, showing large residue divergence from residue 78 to residue 107. (B) Structural comparison between the predicted AlphaFold models of human MRGPR4 and rhesus macaque MRGPRX4. Extracellular view is shown to highlight the structural differences in the binding pocket. (C) Structure of MRGPRX4 (PDB: 7S8P) with the divergent residues from F78 to K96 shown in panel A colored in magenta. As these residues are located near the agonist binding site, rhesus macaque MRGPRX4 may not respond to the agonist of human MRGPRX4. (D) The predicted AlphaFold models of human 5-HT1AR and rhesus macaque 5-HT1AR overlaid well with each other, indicating 5-HT1AR is super conserved across different species. (E) MRPGRX2 loss-of-function mutations highlighted in MRGPRX2-Gq signaling complex (PDB: 7S8N). Polar interactions are depicted by red dashed lines.
Figure 4.
Figure 4.. The shallow agonist binding mode of MRGPRs.
(A) The canonical TM3-ECL2 observed in β2 adrenergic receptor (β2AR) helps stabilize the conformation of ECL2 on the top of the agonist binding pocket (PDB: 3SN6). (B) MRGPRX2 (PDB: 7S8N) only contains a TM4-TM5 disulfide bond. Thus, its ECL2 does not cover the ligand binding pocket. (C) Replacement of large residue W6.48 in β2AR (PDB: 3SN6) to small residue G6.48 in MRGPRX2 (PDB: 7S8N) leads to a close contact between TM6 with TM3, which results in a shallow agonist binding pocket. MRGPRX2 and β2AR are colored by cyan and blue, respectively. The inset shows the interaction between Y3.36 and G6.48, which is important to maintain the active state of MRGPRs. (D) MRGPRs have shallow agonist binding pockets that are far away from the residue 6.48. PDB 7S8N, 7S8L, 7S8P, 8DWG, 7Y12 and 3SN6 are used for MRGPRX2-(R)-ZINC3573, MRGPRX2-cortistatin-14, MRGPRX4, MRGPRX1, MRGPRD and β2AR, respectively.
Figure 5.
Figure 5.. Diverse agonist recognition mechanisms in MRGPRs.
(A) Electrostatic surface representation of MRGPRX2 (PDB: 7S8N), highlighting the negatively charged (colored in red) sub-pocket 1 for agonist recognition. (B) Agonist binding mode of (R)-ZINC-3573 with key MRGPRX2 residues involving in interactions shown in sticks (PDB: 7S8N). (C) Agonist binding mode of cortistatin-14 (PDB: 7S8L), showing corstatin-14 binds to both sub-pocket 1 and sub-pocket 2. (D) Electrostatic surface representation of MRGPRX4 (PDB: 7S8P), highlighting the positively charged (colored in blue) sub-pocket 2 for agonist recognition. (E-G) Agonist binding mode of MRGPRX4 (PDB: 7S8P), MRGPRX1 (PDB: 8DWG) and MRGPRXD (PDB: 7Y12). (H) Predicted AlphaFold models of human MRGPRE, MRGPRF, MRGPRG and MRGPRX3 with residues 5.36/5.37 and 4.60 shown in green sticks. (I), Sequence alignment of the key residues 5.36/5.37 and 4.60 in TM5 and TM4 that are critical for MRGPRs activation.
Figure 6.
Figure 6.. Inactive structural determination for the structure-based drug discovery at MRGPRs.
MRGPRX2 is shown here as an example. The inactive MRGPRX2 structure could be obtained though construct engineering to bind to Nb6 or anti-Bril Fab, both of which increase the molecular weight and facilitate the particle alignment in cryoEM structural determination. The obtained MRGPRX2 inactive structures then could be used as a template for structure-based docking. Both sub-pocket 1 and sub-pocket 2 of MRGPRX2 could be used for docking. However, the antagonist binds to sub-pocket 2 could only inhibit the peptide stimulated MRGPRX2 activation.
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