8dwg

From Proteopedia

(Difference between revisions)

Current revision

CryoEM structure of Gq-coupled MRGPRX1 with peptide ligand BAM8-22 and positive allosteric modulator ML382

Structural highlights

8dwg is a 6 chain structure with sequence from Bos taurus, 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 2.71Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.^[1]

Publication Abstract from PubMed

The human MAS-related G protein-coupled receptor X1 (MRGPRX1) is preferentially expressed in the small-diameter primary sensory neurons and involved in the mediation of nociception and pruritus. Central activation of MRGPRX1 by the endogenous opioid peptide fragment BAM8-22 and its positive allosteric modulator ML382 has been shown to effectively inhibit persistent pain, making MRGPRX1 a promising target for non-opioid pain treatment. However, the activation mechanism of MRGPRX1 is still largely unknown. Here we report three high-resolution cryogenic electron microscopy structures of MRGPRX1-Galphaq in complex with BAM8-22 alone, with BAM8-22 and ML382 simultaneously as well as with a synthetic agonist compound-16. These structures reveal the agonist binding mode for MRGPRX1 and illuminate the structural requirements for positive allosteric modulation. Collectively, our findings provide a molecular understanding of the activation and allosteric modulation of the MRGPRX1 receptor, which could facilitate the structure-based design of non-opioid pain-relieving drugs.

Ligand recognition and allosteric modulation of the human MRGPRX1 receptor.,Liu Y, Cao C, Huang XP, Gumpper RH, Rachman MM, Shih SL, Krumm BE, Zhang S, Shoichet BK, Fay JF, Roth BL Nat Chem Biol. 2023 Apr;19(4):416-422. doi: 10.1038/s41589-022-01173-6. Epub 2022 , Oct 27. PMID:36302898^[2]

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

References

↑ Johnston CA, Kimple AJ, Giguere PM, Siderovski DP. Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2. Structure. 2008 Jul;16(7):1086-94. PMID:18611381 doi:http://dx.doi.org/10.1016/j.str.2008.04.010
↑ Liu Y, Cao C, Huang XP, Gumpper RH, Rachman MM, Shih SL, Krumm BE, Zhang S, Shoichet BK, Fay JF, Roth BL. Ligand recognition and allosteric modulation of the human MRGPRX1 receptor. Nat Chem Biol. 2023 Apr;19(4):416-422. PMID:36302898 doi:10.1038/s41589-022-01173-6

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8dwg"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8dwg]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DWG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DWG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=U39:2-[(cyclopropanesulfonyl)amino]-N-(2-ethoxyphenyl)benzamide'>U39</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.71&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=U39:2-[(cyclopropanesulfonyl)amino]-N-(2-ethoxyphenyl)benzamide'>U39</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8dwg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dwg OCA], [https://pdbe.org/8dwg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dwg RCSB], [https://www.ebi.ac.uk/pdbsum/8dwg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dwg ProSAT]</span></td></tr>
 </table>
 == Function ==
-[https://www.uniprot.org/uniprot/PENK_BOVIN PENK_BOVIN] Neuropeptide that competes with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress.[UniProtKB:P01210]  Neuropeptide that competes with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress.[UniProtKB:P01210]  Met-enkephalin-Arg-Phe neuropeptide acts as a strong ligand of Mu-type opioid receptor OPRM1. Met-enkephalin-Arg-Phe-binding to OPRM1 in the nucleus accumbens of the brain increases activation of OPRM1, leading to long-term synaptic depression of glutamate release.[UniProtKB:P22005]  Increases glutamate release in the striatum and decreases GABA concentration in the striatum.[UniProtKB:P04094]  Increases glutamate release in the striatum.[UniProtKB:P04094]  Enkelytin possesses antibacterial activity against Gram-positive bacteria such as Micrococcus luteus and Bacillus megaterium.<ref>PMID:8654396</ref>
+[https://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.<ref>PMID:18611381</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The human MAS-related G protein-coupled receptor X1 (MRGPRX1) is preferentially expressed in the small-diameter primary sensory neurons and involved in the mediation of nociception and pruritus. Central activation of MRGPRX1 by the endogenous opioid peptide fragment BAM8-22 and its positive allosteric modulator ML382 has been shown to effectively inhibit persistent pain, making MRGPRX1 a promising target for non-opioid pain treatment. However, the activation mechanism of MRGPRX1 is still largely unknown. Here we report three high-resolution cryogenic electron microscopy structures of MRGPRX1-Galphaq in complex with BAM8-22 alone, with BAM8-22 and ML382 simultaneously as well as with a synthetic agonist compound-16. These structures reveal the agonist binding mode for MRGPRX1 and illuminate the structural requirements for positive allosteric modulation. Collectively, our findings provide a molecular understanding of the activation and allosteric modulation of the MRGPRX1 receptor, which could facilitate the structure-based design of non-opioid pain-relieving drugs.
+Ligand recognition and allosteric modulation of the human MRGPRX1 receptor.,Liu Y, Cao C, Huang XP, Gumpper RH, Rachman MM, Shih SL, Krumm BE, Zhang S, Shoichet BK, Fay JF, Roth BL Nat Chem Biol. 2023 Apr;19(4):416-422. doi: 10.1038/s41589-022-01173-6. Epub 2022 , Oct 27. PMID:36302898<ref>PMID:36302898</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 8dwg" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Transducin 3D structures|Transducin 3D structures]]
 == References ==
 <references/>

8dwg

From Proteopedia

Current revision

CryoEM structure of Gq-coupled MRGPRX1 with peptide ligand BAM8-22 and positive allosteric modulator ML382

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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