Editing G protein-coupled receptor (section)

==Structure–function relationships==

[[File:GPCR in membrane.png|right|thumb|500px|Two-dimensional schematic of a generic GPCR set in a [[lipid raft]]. Click the image for higher resolution to see details regarding the locations of important structures.]]
In terms of structure, GPCRs are characterized by an extracellular [[N-terminus]], followed by seven [[transmembrane domain|transmembrane]] (7-TM) [[alpha helix|α-helices]] (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular [[C-terminus]]. The GPCR arranges itself into a [[protein tertiary structure|tertiary structure]] resembling a barrel, with the seven transmembrane helices forming a cavity within the plasma membrane that serves a [[ligand (biochemistry)|ligand]]-binding domain that is often covered by EL-2. Ligands may also bind elsewhere, however, as is the case for bulkier ligands (e.g., [[protein]]s or large [[peptide]]s), which instead interact with the extracellular loops, or, as illustrated by the class C [[metabotropic glutamate receptors]] (mGluRs), the N-terminal tail. The class C GPCRs are distinguished by their large N-terminal tail, which also contains a ligand-binding domain. Upon glutamate-binding to an mGluR, the N-terminal tail undergoes a conformational change that leads to its interaction with the residues of the extracellular loops and TM domains. The eventual effect of all three types of [[agonist]]-induced activation is a change in the relative orientations of the TM helices (likened to a twisting motion) leading to a wider intracellular surface and "revelation" of residues of the intracellular helices and TM domains crucial to signal transduction function (i.e., G-protein coupling). [[Inverse agonist]]s and [[receptor antagonist|antagonist]]s may also bind to a number of different sites, but the eventual effect must be prevention of this TM helix reorientation.<ref name="Trzaskowski2012" />

The structure of the N- and C-terminal tails of GPCRs may also serve important functions beyond ligand-binding. For example, The C-terminus of M<sub>3</sub> muscarinic receptors is sufficient, and the six-amino-acid polybasic (KKKRRK) domain in the C-terminus is necessary for its preassembly with G<sub>q</sub> proteins.<ref name=" pmid=21873996 ">{{cite journal | vauthors = Qin K, Dong C, Wu G, Lambert NA | title = Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers | journal = Nature Chemical Biology | volume = 7 | issue = 10 | pages = 740–7 | date = August 2011 | pmid = 21873996 | pmc = 3177959 | doi = 10.1038/nchembio.642 }}</ref> In particular, the C-terminus often contains [[serine]] (Ser) or [[threonine]] (Thr) residues that, when [[phosphorylation|phosphorylated]], increase the [[affinity (pharmacology)|affinity]] of the intracellular surface for the binding of scaffolding proteins called β-[[arrestin]]s (β-arr).<ref name="pmid2163110">{{cite journal | vauthors = Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ | title = beta-Arrestin: a protein that regulates beta-adrenergic receptor function | journal = Science | volume = 248 | issue = 4962 | pages = 1547–50 | date = June 1990 | pmid = 2163110 | doi = 10.1126/science.2163110 | bibcode = 1990Sci...248.1547L }}</ref> Once bound, β-arrestins both [[sterically]] prevent G-protein coupling and may recruit other proteins, leading to the creation of signaling complexes involved in extracellular-signal regulated kinase ([[extracellular signal-regulated kinases|ERK]]) pathway activation or receptor [[endocytosis]] (internalization). As the phosphorylation of these Ser and Thr residues often occurs as a result of GPCR activation, the β-arr-mediated G-protein-decoupling and internalization of GPCRs are important mechanisms of [[desensitization (medicine)|desensitization]].<ref name="pmid11861753">{{cite journal | vauthors = Luttrell LM, Lefkowitz RJ | title = The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals | journal = Journal of Cell Science | volume = 115 | issue = Pt 3 | pages = 455–65 | date = February 2002 | doi = 10.1242/jcs.115.3.455 | pmid = 11861753 | hdl = 10161/7805 | hdl-access = free }}</ref> In addition, internalized "mega-complexes" consisting of a single GPCR, β-arr(in the tail conformation),<ref name="pmid28223524">{{cite journal | vauthors = Cahill TJ, Thomsen AR, Tarrasch JT, Plouffe B, Nguyen AH, Yang F, Huang LY, Kahsai AW, Bassoni DL, Gavino BJ, Lamerdin JE, Triest S, Shukla AK, Berger B, Little J, Antar A, Blanc A, Qu CX, Chen X, Kawakami K, Inoue A, Aoki J, Steyaert J, Sun JP, Bouvier M, Skiniotis G, Lefkowitz RJ | title = Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 10 | pages = 2562–2567 | date = March 2017 | pmid = 28223524 | pmc = 5347553 | doi = 10.1073/pnas.1701529114 | bibcode = 2017PNAS..114.2562C | doi-access = free }}</ref><ref name="pmid27827372">{{cite journal | vauthors = Kumari P, Srivastava A, Banerjee R, Ghosh E, Gupta P, Ranjan R, Chen X, Gupta B, Gupta C, Jaiman D, Shukla AK | title = Functional competence of a partially engaged GPCR-β-arrestin complex | journal = Nature Communications | volume = 7 | pages = 13416 | date = November 2016 | pmid = 27827372 | pmc = 5105198 | doi = 10.1038/ncomms13416 | bibcode = 2016NatCo...713416K }}</ref> and heterotrimeric G protein exist and may account for protein signaling from endosomes.<ref name="pmid27499021">{{cite journal | vauthors = Thomsen AR, Plouffe B, Cahill TJ, Shukla AK, Tarrasch JT, Dosey AM, Kahsai AW, Strachan RT, Pani B, Mahoney JP, Huang L, Breton B, Heydenreich FM, Sunahara RK, Skiniotis G, Bouvier M, Lefkowitz RJ | title = GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling | journal = Cell | volume = 166 | issue = 4 | pages = 907–919 | date = August 2016 | pmid = 27499021 | pmc = 5418658 | doi = 10.1016/j.cell.2016.07.004 }}</ref><ref name="pmid31740855">{{cite journal | vauthors = Nguyen AH, Thomsen AR, Cahill TJ, Huang R, Huang LY, Marcink T, Clarke OB, Heissel S, Masoudi A, Ben-Hail D, Samaan F, Dandey VP, Tan YZ, Hong C, Mahoney JP, Triest S, Little J, Chen X, Sunahara R, Steyaert J, Molina H, Yu Z, des Georges A, Lefkowitz RJ | title = Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex | journal = Nature Structural & Molecular Biology | volume = 26 | issue = 12 | pages = 1123–1131 | date = December 2019 | pmid = 31740855 | pmc = 7108872 | doi = 10.1038/s41594-019-0330-y }}</ref>

A final common structural theme among GPCRs is [[palmitoylation]] of one or more sites of the C-terminal tail or the intracellular loops. Palmitoylation is the covalent modification of [[cysteine]] (Cys) residues via addition of hydrophobic [[acyl group]]s, and has the effect of targeting the receptor to [[cholesterol]]- and [[sphingolipid]]-rich microdomains of the plasma membrane called [[lipid raft]]s. As many of the downstream transducer and effector molecules of GPCRs (including those involved in [[negative feedback]] pathways) are also targeted to lipid rafts, this has the effect of facilitating rapid receptor signaling.{{cn|date=April 2025}}

GPCRs respond to extracellular signals mediated by a huge diversity of agonists, ranging from proteins to [[biogenic amines]] to [[protons]], but all transduce this signal via a mechanism of G-protein coupling. This is made possible by a [[guanine]]-nucleotide exchange factor ([[guanine nucleotide exchange factor|GEF]]) domain primarily formed by a combination of IL-2 and IL-3 along with adjacent residues of the associated TM helices.{{cn|date=April 2025}}