Proteopedia

7s8l

CryoEM structure of Gq-coupled MRGPRX2 with peptide agonist Cortistatin-14CryoEM structure of Gq-coupled MRGPRX2 with peptide agonist Cortistatin-14

Structural highlights

7s8l is a 6 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.45Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MRGX2_HUMAN Mast cell-specific receptor for basic secretagogues, i.e. cationic amphiphilic drugs, as well as endo- or exogenous peptides, consisting of a basic head group and a hydrophobic core (PubMed:25517090). Recognizes and binds small molecules containing a cyclized tetrahydroisoquinoline (THIQ), such as non-steroidal neuromuscular blocking drugs (NMBDs), including tubocurarine and atracurium. In response to these compounds, mediates pseudo-allergic reactions characterized by histamine release, inflammation and airway contraction (By similarity). Acts as a receptor for a number of other ligands, including peptides and alkaloids, such as cortistatin-14, proadrenomedullin N-terminal peptides PAMP-12 and, at lower extent, PAMP-20, antibacterial protein LL-37, PMX-53 peptide, beta-defensins, and complanadine A.[UniProtKB:Q3KNA1][1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently(1). Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions(2-5). MRGPRX2 couples to both Gi and Gq in mast cells(6). Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq 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 Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

Structure, function and pharmacology of human itch GPCRs.,Cao C, Kang HJ, Singh I, Chen H, Zhang C, Ye W, Hayes BW, Liu J, Gumpper RH, Bender BJ, Slocum ST, Krumm BE, Lansu K, McCorvy JD, Kroeze WK, English JG, DiBerto JF, Olsen RHJ, Huang XP, Zhang S, Liu Y, Kim K, Karpiak J, Jan LY, Abraham SN, Jin J, Shoichet BK, Fay JF, Roth BL Nature. 2021 Dec;600(7887):170-175. doi: 10.1038/s41586-021-04126-6. Epub 2021, Nov 17. PMID:34789874[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Kamohara M, Matsuo A, Takasaki J, Kohda M, Matsumoto M, Matsumoto S, Soga T, Hiyama H, Kobori M, Katou M. Identification of MrgX2 as a human G-protein-coupled receptor for proadrenomedullin N-terminal peptides. Biochem Biophys Res Commun. 2005 May 20;330(4):1146-52. doi:, 10.1016/j.bbrc.2005.03.088. PMID:15823563 doi:http://dx.doi.org/10.1016/j.bbrc.2005.03.088
  2. ↑ Subramanian H, Kashem SW, Collington SJ, Qu H, Lambris JD, Ali H. PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Mol Pharmacol. 2011 Jun;79(6):1005-13. doi: 10.1124/mol.111.071472. Epub 2011 Mar, 11. PMID:21441599 doi:http://dx.doi.org/10.1124/mol.111.071472
  3. ↑ Subramanian H, Gupta K, Guo Q, Price R, Ali H. Mas-related gene X2 (MrgX2) is a novel G protein-coupled receptor for the antimicrobial peptide LL-37 in human mast cells: resistance to receptor phosphorylation, desensitization, and internalization. J Biol Chem. 2011 Dec 30;286(52):44739-49. doi: 10.1074/jbc.M111.277152. Epub, 2011 Nov 8. PMID:22069323 doi:http://dx.doi.org/10.1074/jbc.M111.277152
  4. ↑ Subramanian H, Gupta K, Lee D, Bayir AK, Ahn H, Ali H. beta-Defensins activate human mast cells via Mas-related gene X2. J Immunol. 2013 Jul 1;191(1):345-52. doi: 10.4049/jimmunol.1300023. Epub 2013 May, 22. PMID:23698749 doi:http://dx.doi.org/10.4049/jimmunol.1300023
  5. ↑ Johnson T, Siegel D. Complanadine A, a selective agonist for the Mas-related G protein-coupled receptor X2. Bioorg Med Chem Lett. 2014 Aug 1;24(15):3512-5. doi: 10.1016/j.bmcl.2014.05.060. , Epub 2014 May 27. PMID:24930830 doi:http://dx.doi.org/10.1016/j.bmcl.2014.05.060
  6. ↑ McNeil BD, Pundir P, Meeker S, Han L, Undem BJ, Kulka M, Dong X. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015 Mar 12;519(7542):237-41. doi: 10.1038/nature14022. Epub 2014 Dec 17. PMID:25517090 doi:http://dx.doi.org/10.1038/nature14022
  7. ↑ Robas N, Mead E, Fidock M. MrgX2 is a high potency cortistatin receptor expressed in dorsal root ganglion. J Biol Chem. 2003 Nov 7;278(45):44400-4. doi: 10.1074/jbc.M302456200. Epub 2003, Aug 12. PMID:12915402 doi:http://dx.doi.org/10.1074/jbc.M302456200
  8. ↑ Cao C, Kang HJ, Singh I, Chen H, Zhang C, Ye W, Hayes BW, Liu J, Gumpper RH, Bender BJ, Slocum ST, Krumm BE, Lansu K, McCorvy JD, Kroeze WK, English JG, DiBerto JF, Olsen RHJ, Huang XP, Zhang S, Liu Y, Kim K, Karpiak J, Jan LY, Abraham SN, Jin J, Shoichet BK, Fay JF, Roth BL. Structure, function and pharmacology of human itch GPCRs. Nature. 2021 Dec;600(7887):170-175. doi: 10.1038/s41586-021-04126-6. Epub 2021, Nov 17. PMID:34789874 doi:http://dx.doi.org/10.1038/s41586-021-04126-6

7s8l, resolution 2.45Å

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