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G protein-coupled receptors, often abbreviated GPCRs, are an abundant superfamily of proteins also known as seven-transmembrane domain receptors, 7TM receptors, 7 pass transmembrane receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors (GPLRs). G protein-coupled receptors are cell surface signalling proteins involved in many physiological functions and in multiple diseases. They are also the target of the majority of all modern medicinal drugs^[1][2]. The extracellular side is generally where the ligand enters for binding. On the intracellular side they interact with G proteins involved in signaling induced by the binding of the ligand.

Illustrating their importance and the largesse of the superfamily, there are roughly 800 known members of the superfamily in the human genome alone — estimated to be 4% of human protein-coding genes. Members are further subclassified into one of five families of GPCRs^[3].

Rhodopsin shares similar membrane topology with the members of the superfamily, specifically family A of the G protein-coupled receptors which include the seven transmembrane helices, an extracellular N-terminus and cytoplasmic C-terminus^[4].

Contents 1 3D Structures of G protein-coupled receptors 1.1 Rhodopsins 1.2 β2 adrenergic receptor 1.3 β1 adrenergic receptor 1.4 A2A adenosine receptor 1.5 Histamine H1 receptor 1.6 Metabotropic glutamate receptors 1.7 Sphingosine 1-phosphate Receptor 1.8 Dopamine D3 Receptor 1.9 CXCR4 Chemokine Receptor 1.10 Muscarinic M2 receptor 1.11 Muscarinic M3 receptor 1.12 kappa opioid receptor 1.13 mu opioid receptor 1.14 delta opioid receptor 1.15 nociceptin/orphanin FQ receptor 2 Nobel Prize Related to the Structures 3 References and Notes 4 See Also 5 Additional Literature 6 External Resources

3D Structures of G protein-coupled receptors

Rhodopsins

Rhodopsins are listed individually in a section on the Rhodopsin topic page 3D structures in Rhodopsin.

β2 adrenergic receptor

	Show:Asymmetric Unit Biological Assembly   Export Animated Image An activated G protein-coupled receptor (human β-2 adrenergic receptor in blue ) in a complex with a heterotrimeric G protein (3 subunits:reddish to orange-brown) and hormone (gold) (3sn6), resolution 3.2Å. The boundaries of the membrane in which the GPCR sits are represented in light green.

• A topic page concerning the Beta-2 Adrenergic Receptor
• The human β2 adrenergic receptor bound to a G-protein (3sn6) is featured in a scene on the right, and additional structures are on the Adrenergic receptor page.

β1 adrenergic receptor

3D structures in Adrenergic receptor.

A2A adenosine receptor

• 3eml - human A2A adenosine receptor bound to antagaonist ZM241385
• 3pwh - thermostabilized human A2A adenosine receptor
• 3rey - thermostabilized human A2A adenosine receptor in complex with the xanthines xanthine amine congener
• 3rfm - thermostabilized human A2A adenosine receptor in complex with caffeine
• 3qak - human A2A adenosine receptor bound to an agonist UK-432097
• 3vg9 - human A2A adenosine receptor in complex with a mouse monoclonal-antibody Fab fragment, Fab2838
• 3vga - human A2A adenosine receptor in complex with a mouse monoclonal-antibody Fab fragment, Fab2838
• 2yd0 - human A2A adenosine receptor in complex with the endogenous agonist adenosine
• 2ydv - human A2A adenosine receptor in complex with synthetic agonist NECA
• 4eiy - human A2A adenosine receptor thermostabilized by replacing its third intracellular loop with apocytochrome b(562)RIL

Histamine H1 receptor

• 3rze - human histamine H1 receptor
• Histamine H1 receptor

Metabotropic glutamate receptors

• 4or2 - human mGlu₁ receptor seven-transmembrane domain bound to a negative allosteric modulator

Sphingosine 1-phosphate Receptor

• 3v2w,3v2y - human sphingosine 1-phosphate receptor 1 with a bound sphingolipid mimic

Dopamine D3 Receptor

• Dopamine receptor

CXCR4 Chemokine Receptor

• CXC chemokine receptor type 4

Muscarinic M2 receptor

• 3uon - human muscarinic M2 receptor, complexed with an antagonist 3-quinuclidinyl-benzilate

Muscarinic M3 receptor

• 4daj - rat muscarinic M3 receptor, complexed with bronchodilator drug tiotropium

kappa opioid receptor

• 4djh - human kappa opioid receptor, complexed with antagonist JDTic

mu opioid receptor

• 4dkl - mouse mu opioid receptor, complexed with an irreversible morphinan antagonist

delta opioid receptor

• 4ej4 - mouse delta opioid receptor, complexed with naltrindole

nociceptin/orphanin FQ receptor

• 4ea3 - human nociceptin/orphanin FQ receptor, complexed with a peptide mimetic antagonist compound 24

3kj6 3ny8 3ny9 3nya 1bl1 1d6g 1ddv 1dep

1edw 1edx 1ewk 1ewt 1ewv 1f88 1fdf 1fjr 1gzm 1hll 1ho9 1hod 1hof 1hzn

Nobel Prize Related to the Structures

Robert J. Lefkowitz and Brian K. Kobilka share the 2012 Nobel Prize in Chemistry for work on GPCRs that includes solving the first structures of a ligand-activated GPCR (2r4r, 2r4s, & 2rh1 in 2007)^[5][6][7] and the first activated GPCR in complex with its G protein (3sn6 in 2011)^{[8][9][10][11]}. A detailed description of the laureates' body of work on this class of receptors with images is here.

References and Notes

1. ↑ Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. PMID:17139284 doi:10.1038/nrd2199
2. ↑ Peeters MC, van Westen GJ, Li Q, IJzerman AP. Importance of the extracellular loops in G protein-coupled receptors for ligand recognition and receptor activation. Trends Pharmacol Sci. 2011 Jan;32(1):35-42. PMID:21075459 doi:10.1016/j.tips.2010.10.001
3. ↑ Millar RP, Newton CL. The year in G protein-coupled receptor research. Mol Endocrinol. 2010 Jan;24(1):261-74. Epub 2009 Dec 17. PMID:20019124 doi:10.1210/me.2009-0473
4. ↑ Kristiansen K. Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function. Pharmacol Ther. 2004 Jul;103(1):21-80. PMID:15251227 doi:10.1016/j.pharmthera.2004.05.002
5. ↑ Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science. 2007 Nov 23;318(5854):1258-65. Epub 2007 Oct 25. PMID:17962520
6. ↑ Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK. GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science. 2007 Nov 23;318(5854):1266-73. Epub 2007 Oct 25. PMID:17962519
7. ↑ Ranganathan R. Biochemistry. Signaling across the cell membrane. Science. 2007 Nov 23;318(5854):1253-4. PMID:18033872 doi:10.1126/science.1151656
8. ↑ Schwartz TW, Sakmar TP. Structural biology: snapshot of a signalling complex. Nature. 2011 Sep 28;477(7366):540-1. doi: 10.1038/477540a. PMID:21956322 doi:10.1038/477540a
9. ↑ 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. Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature. 2011 Jul 19;477(7366):549-55. doi: 10.1038/nature10361. PMID:21772288 doi:10.1038/nature10361
10. ↑ Chung KY, Rasmussen SG, Liu T, Li S, DeVree BT, Chae PS, Calinski D, Kobilka BK, Woods VL Jr, Sunahara RK. Conformational changes in the G protein Gs induced by the beta2 adrenergic receptor. Nature. 2011 Sep 28;477(7366):611-5. doi: 10.1038/nature10488. PMID:21956331 doi:10.1038/nature10488
11. ↑ Schwartz TW, Sakmar TP. Structural biology: snapshot of a signalling complex. Nature. 2011 Sep 28;477(7366):540-1. doi: 10.1038/477540a. PMID:21956322 doi:10.1038/477540a

See Also

• Nobel Prizes for 3D Molecular Structure
• Highest impact structures of all time
• G proteins
• Rhodopsin
• GTP-binding protein
• Pharmaceutical Drugs
• Membrane proteins
• Hormone
• Ligand Binding N-Terminal of Metabotropic Glutamate Receptors

Additional Literature

• Carpenter B, Tate CG. Active state structures of G protein-coupled receptors highlight the similarities and differences in the G protein and arrestin coupling interfaces. Curr Opin Struct Biol. 2017 May 5;45:124-132. doi: 10.1016/j.sbi.2017.04.010. PMID:28482214 doi:http://dx.doi.org/10.1016/j.sbi.2017.04.010

External Resources

• Robert J. Lefkowitz and Brian K. Kobilka share the 2012 Nobel Prize in Chemistry for work on GPCRs that includes solving the first structures of a ligand-activated GPCR (2007) and the first activated GPCR in complex with its G protein (2011). A detailed description of the laureates' body of work on this class of receptors with images is here.
• The April 2008 RCSB PDB Molecule of the Month feature on Adrenergic Receptors by David S. Goodsell is 10.2210/rcsb_pdb/mom_2008_4.
• GPCRDB: database contains sequences, ligand binding constants and mutations, in addition GPCR multiple sequence alignments and homology models. Moreover, the site contains useful files where lysozyme and other inserts which are commonly used in the difficult process of crystallizing these transmembrane structures have been removed from the structures.
• GPCR Network site with tracking chart of ongoing structural programs
• The GPCR-SSFE Database: A Homology Model Resource for G-Protein Coupled Receptors
• The blog of the Computational Chemical Biology group at the EMBL-EBI does an excellent job tracking the new GPCR structures as they are emerging.
• Emerald Biosystems Blog that features solved structures and on another page features techniques and amounts needed for crystallization of a number of them.
• A 2012 article from Scripps Research Institute that covers a lot of history of solving the structures of GPCRs and their importance.
• A 2012 article from the Protein Structure Initiative on the screening technique to identify stabilizing fusion partners for solving GPCR structure.
• A 2011 article in Nature entitiled 'Cell Signalling Caught in the Act' describing the first determination of an activated GPCR — the β2 adrenergic receptor (β2AR) — in a complex with its G protein.
• tinyGRAP GPCR mutant database
• GPCR-OKB: GPCR Oligomerization Knowledge Base
• GPCR Natural Variants Database (NaVa)
• The PRED-GPCR server for GPCR recognition and family classification.
• GLASS database: a comprehensive database for experimentally validated GPCR-ligand associations
• GPCR-ModSim is a webserver for computational modeling and simulation of G-Protein Coupled Receptors (GPCRs). Models from sequence and also lets you place the models in a phospholipid bilayer and model them using Molecular Dynamics.