8g05

From Proteopedia

(Difference between revisions)

Revision as of 14:35, 6 November 2024

Cryo-EM structure of an orphan GPCR-Gi protein signaling complex

Structural highlights

8g05 is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GPR84_HUMAN G protein-coupled receptor that responds endogenously to dietary fatty acids or nutrient, specifically medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent agonists (PubMed:16966319). In immune cells, functions as a pro-inflammatory receptor via 6-OAU and promotes the expression of pro-inflammatory mediators such as TNFalpha, IL-6 and IL-12B as well as stimulating chemotactic responses through activation of signaling mediators AKT, ERK and NF-kappa-B (By similarity). In addition, triggers increased bacterial adhesion and phagocytosis in macrophages and regulates pro-inflammatory function via enhancing NLRP3 inflammasome activation (By similarity). Plays also an important role in inflammation by modulating neutrophil functions (By similarity). Mechanistically, promotes neutrophil chemotaxis, reactive oxygen species (ROS) production and degranulation via LYN-AKT/ERK pathway (By similarity). To regulate ROS, communicates with the two formyl peptide receptors FPR2 and FPR1 to control the NADPH oxidase activity in neutrophils (PubMed:33789297).[UniProtKB:Q8CIM5]^[1] ^[2]

Publication Abstract from PubMed

GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely pro-inflammatory, which can augment inflammatory response, and GPR84 also functions as a pro-phagocytic receptor to enhance phagocytic activities of macrophages. In this study, we show that the activation of GPR84 by the synthetic agonist 6-OAU can synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. We also determine a high-resolution structure of the GPR84-G(i) signaling complex with 6-OAU. This structure reveals an occluded binding pocket for 6-OAU, the molecular basis of receptor activation involving non-conserved structural motifs of GPR84, and an unusual G(i)-coupling interface. Together with computational docking and simulations studies, this structure also suggests a mechanism for the high selectivity of GPR84 for MCFAs and a potential routes of ligand binding and dissociation. These results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.

Pro-phagocytic function and structural basis of GPR84 signaling.,Zhang X, Wang Y, Supekar S, Cao X, Zhou J, Dang J, Chen S, Jenkins L, Marsango S, Li X, Liu G, Milligan G, Feng M, Fan H, Gong W, Zhang C Nat Commun. 2023 Sep 14;14(1):5706. doi: 10.1038/s41467-023-41201-0. PMID:37709767^[3]

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

References

↑ Wang J, Wu X, Simonavicius N, Tian H, Ling L. Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J Biol Chem. 2006 Nov 10;281(45):34457-64. PMID:16966319 doi:10.1074/jbc.M608019200
↑ Mårtensson J, Sundqvist M, Manandhar A, Ieremias L, Zhang L, Ulven T, Xie X, Björkman L, Forsman H. The Two Formyl Peptide Receptors Differently Regulate GPR84-Mediated Neutrophil NADPH Oxidase Activity. J Innate Immun. 2021;13(4):242-256. PMID:33789297 doi:10.1159/000514887
↑ Zhang X, Wang Y, Supekar S, Cao X, Zhou J, Dang J, Chen S, Jenkins L, Marsango S, Li X, Liu G, Milligan G, Feng M, Fan H, Gong W, Zhang C. Pro-phagocytic function and structural basis of GPR84 signaling. Nat Commun. 2023 Sep 14;14(1):5706. PMID:37709767 doi:10.1038/s41467-023-41201-0

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8g05"

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[8g05]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G05 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G05 FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=YI9:6-(octylamino)pyrimidine-2,4(3H,5H)-dione'>YI9</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=YI9:6-(octylamino)-5~{H}-pyrimidine-2,4-dione'>YI9</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=8g05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g05 OCA], [https://pdbe.org/8g05 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g05 RCSB], [https://www.ebi.ac.uk/pdbsum/8g05 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g05 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[https://www.uniprot.org/uniprot/GPR84_HUMAN GPR84_HUMAN] Receptor for medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent agonists. Not activated by short-chain and long-chain saturated and unsaturated FFAs. Activation by medium-chain free fatty acid is coupled to a pertussis toxin sensitive G(i/o) protein pathway. May have important roles in processes from fatty acid metabolism to regulation of the immune system.<ref>PMID:16966319</ref>
+[https://www.uniprot.org/uniprot/GPR84_HUMAN GPR84_HUMAN] G protein-coupled receptor that responds endogenously to dietary fatty acids or nutrient, specifically medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent agonists (PubMed:16966319). In immune cells, functions as a pro-inflammatory receptor via 6-OAU and promotes the expression of pro-inflammatory mediators such as TNFalpha, IL-6 and IL-12B as well as stimulating chemotactic responses through activation of signaling mediators AKT, ERK and NF-kappa-B (By similarity). In addition, triggers increased bacterial adhesion and phagocytosis in macrophages and regulates pro-inflammatory function via enhancing NLRP3 inflammasome activation (By similarity). Plays also an important role in inflammation by modulating neutrophil functions (By similarity). Mechanistically, promotes neutrophil chemotaxis, reactive oxygen species (ROS) production and degranulation via LYN-AKT/ERK pathway (By similarity). To regulate ROS, communicates with the two formyl peptide receptors FPR2 and FPR1 to control the NADPH oxidase activity in neutrophils (PubMed:33789297).[UniProtKB:Q8CIM5]<ref>PMID:16966319</ref> <ref>PMID:33789297</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

8g05

From Proteopedia

Revision as of 14:35, 6 November 2024

Cryo-EM structure of an orphan GPCR-Gi protein signaling complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox