Editing G protein-coupled receptor (section)

==Receptor structure==

GPCRs are [[integral membrane protein]]s that possess seven membrane-spanning domains or [[transmembrane helix|transmembrane helices]].<ref name="pmid 23407534">{{cite journal | vauthors = Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM | title = Molecular signatures of G-protein-coupled receptors | journal = Nature | volume = 494 | issue = 7436 | pages = 185–94 | date = February 2013 | pmid = 23407534 | doi = 10.1038/nature11896 | bibcode = 2013Natur.494..185V | s2cid = 4423750 }}</ref><ref name="pmid24359917">{{cite journal | vauthors = Hollenstein K, de Graaf C, Bortolato A, Wang MW, Marshall FH, Stevens RC | title = Insights into the structure of class B GPCRs | journal = Trends in Pharmacological Sciences | volume = 35 | issue = 1 | pages = 12–22 | date = January 2014 | pmid = 24359917 | pmc = 3931419 | doi = 10.1016/j.tips.2013.11.001 }}</ref> The extracellular parts of the receptor can be [[glycosylation|glycosylated]]. These extracellular loops also contain two highly conserved [[cysteine]] residues that form [[disulfide bond]]s to stabilize the receptor structure. Some seven-transmembrane helix proteins ([[channelrhodopsin]]) that resemble GPCRs may contain ion channels, within their protein.{{cn|date=April 2025}}

In 2000, the first crystal structure of a mammalian GPCR, that of bovine [[rhodopsin]] ({{PDB2|1F88}}), was solved.<ref name="pmid10926528">{{cite journal | vauthors = Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M | title = Crystal structure of rhodopsin: A G protein-coupled receptor | journal = Science | volume = 289 | issue = 5480 | pages = 739–45 | date = August 2000 | pmid = 10926528 | doi = 10.1126/science.289.5480.739 | bibcode = 2000Sci...289..739P | citeseerx = 10.1.1.1012.2275 }}</ref> In 2007, the first structure of a human GPCR was solved <ref name="Rasmussen_2007">{{cite journal | vauthors = Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK | title = Crystal structure of the human beta2 adrenergic G-protein-coupled receptor | journal = Nature | volume = 450 | issue = 7168 | pages = 383–7 | date = November 2007 | pmid = 17952055 | doi = 10.1038/nature06325 | bibcode = 2007Natur.450..383R | s2cid = 4407117 }}</ref><ref name="Cherezov_2007">{{cite journal | vauthors = Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC | title = High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor | journal = Science | volume = 318 | issue = 5854 | pages = 1258–65 | date = November 2007 | pmid = 17962520 | pmc = 2583103 | doi = 10.1126/science.1150577 | bibcode = 2007Sci...318.1258C }}</ref><ref name="Rosenbaum_2007">{{cite journal | vauthors = Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK | s2cid = 1559802 | title = GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function | journal = Science | volume = 318 | issue = 5854 | pages = 1266–73 | date = November 2007 | pmid = 17962519 | doi = 10.1126/science.1150609 | bibcode = 2007Sci...318.1266R | doi-access = free }}</ref> This human [[beta-2 adrenergic receptor|β<sub>2</sub>-adrenergic receptor]] GPCR structure proved highly similar to the bovine rhodopsin. The structures of activated or agonist-bound GPCRs have also been determined.<ref name="pmid21228869">{{cite journal | vauthors = Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS, Devree BT, Rosenbaum DM, Thian FS, Kobilka TS, Schnapp A, Konetzki I, Sunahara RK, Gellman SH, Pautsch A, Steyaert J, Weis WI, Kobilka BK | title = Structure of a nanobody-stabilized active state of the β(2) adrenoceptor | journal = Nature | volume = 469 | issue = 7329 | pages = 175–80 | date = January 2011 | pmid = 21228869 | pmc = 3058308 | doi = 10.1038/nature09648 | bibcode = 2011Natur.469..175R }}</ref><ref name="pmid21228876">{{cite journal | vauthors = Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DH, Rasmussen SG, Choi HJ, Devree BT, Sunahara RK, Chae PS, Gellman SH, Dror RO, Shaw DE, Weis WI, Caffrey M, Gmeiner P, Kobilka BK | title = Structure and function of an irreversible agonist-β(2) adrenoceptor complex | journal = Nature | volume = 469 | issue = 7329 | pages = 236–40 | date = January 2011 | pmid = 21228876 | pmc = 3074335 | doi = 10.1038/nature09665 | bibcode = 2011Natur.469..236R }}</ref><ref name="pmid21228877">{{cite journal | vauthors = Warne T, Moukhametzianov R, Baker JG, Nehmé R, Edwards PC, Leslie AG, Schertler GF, Tate CG | title = The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor | journal = Nature | volume = 469 | issue = 7329 | pages = 241–4 | date = January 2011 | pmid = 21228877 | pmc = 3023143 | doi = 10.1038/nature09746 | bibcode = 2011Natur.469..241W }}</ref><ref name="pmid21393508">{{cite journal | vauthors = Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao ZG, Cherezov V, Stevens RC | title = Structure of an agonist-bound human A2A adenosine receptor | journal = Science | volume = 332 | issue = 6027 | pages = 322–7 | date = April 2011 | pmid = 21393508 | pmc = 3086811 | doi = 10.1126/science.1202793 | bibcode = 2011Sci...332..322X }}</ref> These structures indicate how ligand binding at the extracellular side of a receptor leads to conformational changes in the cytoplasmic side of the receptor. The biggest change is an outward movement of the cytoplasmic part of the 5th and 6th transmembrane helix (TM5 and TM6). The structure of activated beta-2 adrenergic receptor in complex with G<sub>s</sub> confirmed that the Gα binds to a cavity created by this movement.<ref name="pmid21772288">{{cite journal | vauthors = Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK | title = Crystal structure of the β2 adrenergic receptor-Gs protein complex | journal = Nature | volume = 477 | issue = 7366 | pages = 549–55 | date = July 2011 | pmid = 21772288 | pmc = 3184188 | doi = 10.1038/nature10361 | bibcode = 2011Natur.477..549R }}</ref>

GPCRs exhibit a similar structure to some other proteins with seven [[transmembrane domain]]s, such as [[microbial rhodopsin]]s and adiponectin receptors 1 and 2 ([[ADIPOR1]] and [[ADIPOR2]]). However, these 7TMH (7-transmembrane helices) receptors and channels do not associate with [[G protein]]s. In addition, ADIPOR1 and ADIPOR2 are oriented oppositely to GPCRs in the membrane (i.e. GPCRs usually have an extracellular [[N-terminus]], cytoplasmic [[C-terminus]], whereas ADIPORs are inverted).<ref name="pmid12802337">{{cite journal | vauthors = Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T | title = Cloning of adiponectin receptors that mediate antidiabetic metabolic effects | journal = Nature | volume = 423 | issue = 6941 | pages = 762–9 | date = June 2003 | pmid = 12802337 | doi = 10.1038/nature01705 | bibcode = 2003Natur.423..762Y | s2cid = 52860797 }}</ref>