View source for 8id4


==Cryo-EM structure of the linoleic acid bound GPR120-Gi complex==
<StructureSection load='8id4' size='340' side='right'caption='[[8id4]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8id4]] 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=8ID4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ID4 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EIC:LINOLEIC+ACID'>EIC</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=8id4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8id4 OCA], [https://pdbe.org/8id4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8id4 RCSB], [https://www.ebi.ac.uk/pdbsum/8id4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8id4 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FFAR4_HUMAN FFAR4_HUMAN] G-protein-coupled receptor for long-chain fatty acids (LCFAs) with a major role in adipogenesis, energy metabolism and inflammation. Signals via G-protein and beta-arrestin pathways (PubMed:22282525, PubMed:24742677, PubMed:27852822, PubMed:24817122, PubMed:22343897). LCFAs sensing initiates activation of phosphoinositidase C-linked G proteins GNAQ and GNA11 (G(q)/G(11)), inducing a variety of cellular responses via second messenger pathways such as intracellular calcium mobilization, modulation of cyclic adenosine monophosphate (cAMP) production, and mitogen-activated protein kinases (MAPKs) (PubMed:27852822, PubMed:22343897, PubMed:22282525, PubMed:24742677). After LCFAs binding, associates with beta-arrestin ARRB2 that acts as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis (PubMed:22282525, PubMed:24817122). In response to dietary fats, plays an important role in the regulation of adipocyte proliferation and differentiation (By similarity). Acts as a receptor for omega-3 polyunsaturated fatty acids (PUFAs) at primary cilium of perivascular preadipocytes, initiating an adipogenic program via cAMP and CTCF-dependent chromatin remodeling that ultimately results in transcriptional activation of adipogenic genes and cell cycle entry (By similarity). Induces differentiation of brown adipocytes probably via autocrine and endocrine functions of FGF21 hormone (By similarity). Activates brown adipocytes by initiating intracellular calcium signaling that leads to mitochondrial depolarization and fission, and overall increased mitochondrial respiration (By similarity). Consequently stimulates fatty acid uptake and oxidation in mitochondria together with UCP1-mediated thermogenic respiration, eventually reducing fat mass (By similarity). Regulates bi-potential differentiation of bone marrow mesenchymal stem cells toward osteoblasts or adipocytes likely by up-regulating distinct integrins (By similarity). In response to dietary fats regulates hormone secretion and appetite (By similarity). Stimulates GIP and GLP1 secretion from enteroendocrine cells as well as GCG secretion in pancreatic alpha cells, thereby playing a role in the regulation of blood glucose levels (By similarity). Negatively regulates glucose-induced SST secretion in pancreatic delta cells (By similarity). Mediates LCFAs inhibition of GHRL secretion, an appetite-controlling hormone (By similarity). In taste buds, contributes to sensing of dietary fatty acids by the gustatory system (By similarity). During the inflammatory response, promotes anti-inflammatory M2 macrophage differentiation in adipose tissue (By similarity). Mediates the anti-inflammatory effects of omega-3 PUFAs via inhibition of NLRP3 inflammasome activation (PubMed:23809162). In this pathway, interacts with adapter protein ARRB2 and inhibits the priming step triggered by Toll-like receptors (TLRs) at the level of TAK1 and TAB1 (By similarity). Further inhibits the activation step when ARRB2 directly associates with NLRP3, leading to inhibition of pro-inflammatory cytokine release (PubMed:23809162). Mediates LCFAs anti-apoptotic effects (By similarity).[UniProtKB:Q7TMA4]<ref>PMID:22282525</ref> <ref>PMID:22343897</ref> <ref>PMID:23809162</ref> <ref>PMID:24742677</ref> <ref>PMID:24817122</ref> <ref>PMID:27852822</ref>   Receptor for LCFAs decoupled from G-protein signaling. May signal through beta-arrestin pathway. After LCFAs binding, associates with beta-arrestin ARRB2 that may act as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis.<ref>PMID:22282525</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many via engagement with more than 40 GPCRs. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, involving with a spectrum of metabolic diseases. Here, we report six cryo-EM structures of GPR120 in complex with FA hormones or TUG891 and G(i) or G(iq) trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds and may facilitate rational drug design targeting to GPR120.

Unsaturated bond recognition leads to biased signal in a fatty acid receptor.,Mao C, Xiao P, Tao XN, Qin J, He QT, Zhang C, Guo SC, Du YQ, Chen LN, Shen DD, Yang ZS, Zhang HQ, Huang SM, He YH, Cheng J, Zhong YN, Shang P, Chen J, Zhang DL, Wang QL, Liu MX, Li GY, Guo Y, Xu HE, Wang C, Zhang C, Feng S, Yu X, Zhang Y, Sun JP Science. 2023 Mar 2:eadd6220. doi: 10.1126/science.add6220. PMID:36862765<ref>PMID:36862765</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8id4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: He Q]]
[[Category: Mao C]]
[[Category: Qin J]]
[[Category: Sun J]]
[[Category: Tao X]]
[[Category: Xiao P]]
[[Category: Yu X]]
[[Category: Zhang C]]
[[Category: Zhang Y]]