7S8P

CryoEM structure of Gq-coupled MRGPRX4 with small molecule agonist MS47134

Summary for 7S8P

• Entry DOI: 10.2210/pdb7s8p/pdb
• EMDB information: 24900
• Descriptor: Gs-mini-Gq chimera, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 157810.55

Authors

Cao, C.,Fay, J.F.,Gumpper, R.H.,Roth, B.L. (deposition date: 2021-09-18, release date: 2021-11-17, Last modification date: 2025-06-04)

Primary citation

Cao, C.,Kang, H.J.,Singh, I.,Chen, H.,Zhang, C.,Ye, W.,Hayes, B.W.,Liu, J.,Gumpper, R.H.,Bender, B.J.,Slocum, S.T.,Krumm, B.E.,Lansu, K.,McCorvy, J.D.,Kroeze, W.K.,English, J.G.,DiBerto, J.F.,Olsen, R.H.J.,Huang, X.P.,Zhang, S.,Liu, Y.,Kim, K.,Karpiak, J.,Jan, L.Y.,Abraham, S.N.,Jin, J.,Shoichet, B.K.,Fay, J.F.,Roth, B.L.
Structure, function and pharmacology of human itch GPCRs.
Nature, 600:170-175, 2021

PubMed Abstract: The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions. MRGPRX2 couples to both G and G in mast cells. Here we describe agonist-stabilized structures of MRGPRX2 coupled to G and G in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and G. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

PubMed: 34789874
DOI: 10.1038/s41586-021-04126-6

Experimental method

ELECTRON MICROSCOPY (2.6 Å)