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Research Themes Drug discovery

G Protein-Coupled Receptors

SBKB [doi:10.3942/psi_sgkb/fm_2012_5]
Featured System - May 2012
Short description: In the past five years, the field of GPCR structure has exploded.

In the past five years, the field of GPCR structure has exploded. GPCRs (G protein-coupled receptors) are small membrane-spanning proteins, with most of their surface buried inside the membrane. This makes them notoriously difficult to crystallize. However, there is a great incentive to determine these structures: GPCRs are at the center of signaling pathways that control all manner of essential processes, ranging from vision to carcinogenesis, and thus are important targets for therapeutic intervention. The structure of rhodopsin in 2000 set the stage, giving the first glimpse at their structure. Recently, the development of clever engineering techniques, such as fusing soluble proteins to the receptor or decorating them with antibodies or nanobodies, have provided crystallographic structures for a wide range of GPCRs with diffusable ligands.

Anatomy of a GPCR

By comparing the different GPCR structures, researchers at the PSI GPCR Network have revealed a few common themes in their form and function, as shown here on the beta2 adrenergic receptor (PDB entry 2rh1). As expected, all have the characteristic seven alpha helices passing up and down through the membrane, connected by loops that extend into the surrounding solvent on both sides of the membrane. Several of the helices are punctuated by proline amino acids (shown here in magenta) that form kinks in the helices. These kinks perform two functions. First, they redirect the helices inwards, helping to form a more compact structure. Also, PSI researchers have found that these kinks divide the receptor into two modules. The extracellular module (colored red here) binds to ligands, and tends to be rather different when comparing different GPCRs, the intracellular module (colored blue here) is quite similar in different GPCRs, reflecting the need for the different receptors to interact with a common set of G proteins.

G-proteins and GPCR

GPCR molecules bind to their ligands, then transmit this signal across the membrane to heterotrimeric G proteins. When the G protein binds to the activated GPCR, it loses a bound GDP molecule, replaces it with GTP, and falls into two pieces. The activated G proteins then trigger a cascade of signals inside the cell...until the GTP breaks down into GDP. This structure (PDB entry 3sn6) shows the interaction of a beta2 adrenergic receptor (in pink) with its G protein (in blue). The structure captures the complex in the middle of the process of signaling, after the GDP has been lost, but before it picks up a new GTP.

Two Receptors are Better than One

Nothing is ever simple in biology, and GPCRs are no exception. Signaling by GPCRs may be tuned through the formation of dimers: homodimers of one type of GPCR and heterodimers composed of two different GPCRs. The structures of CXCR4, such as the one shown here from PDB entry 3odu, may be a glimpse of how these dimers form. So far, this is the only GPCR that has formed a side-by-side dimer that is consistent with the way that the receptor binds in the membrane--all the other structures form head-to-tail dimers. This is not surprising, however, since the surfaces of GPCRs are very sticky and do strange things when they are separated from their membranes.

Ligand Binding

In spite of their similarities, each of these GPCRs has a different job: each must bind to one particular type of ligand. By comparing the different GPCR structures, PSI researchers have discovered that the second extracellular loop is particularly important. This loop is quite different in the different GPCR structures. For instance, in rhodopsin (PDB entry 1f88), the loop (shown here in bright green) is closed tightly over the retinal cofactor (shown here in black), but in the other GPCRs with diffusable ligands, it often forms a more open structure. To compare the structures of these different receptors, the JSmol tab below displays an interactive JSmol.

G-Protein-Coupled Receptors (PDB entries 1f88, 3eml, 2vt4, 2rh1, 3odu, 3pbl, 3rze, 4djh, 4dkl, 4ea3 & 3v2y)

Eleven different GPCR structures are superimposed in this Jmol. As you flip through the structures, notice the similarity in the membrane-spanning helices (shown in pink), and the diversity in the second extracellular loop (in bright green). In each case, the ligand is shown in spacefilling representation with atomic colors.


  1. Katritch, V., Cherezov, V. & Stevens, R. C. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol. Sci. 33, 17-27 (2012).

References to Structures

  1. 1f88 - Palczewski, K., et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739-745 (2000).

  2. 3eml - Jaakola, V. P., et al. The 2.6 angstrom crystal structure of human A2A adenosine receptor bound to an antagonist. Science 322, 1211-1217 (2008).

  3. 2vt4 - Warne, A., et al. Structure of the beta1-adrenergic G protein-coupled receptor. Nature 454, 486-491 (2008).

  4. 2rh1 - Cherezov, V., et al. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318, 1258-1265 (2007).

  5. 3odu - Wu, B. et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330, 1066-1071 (2010).

  6. 3pbl - Chien, E. Y., et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330, 1091-1095 (2010).

  7. 3rze - Shimamura, T. Structure of the human histamine H1 receptor complex with doxepin. Nature 467, 65-70 (2011).

  8. 4djh - Wu, H., et al. Structure of the human kappa opioid receptor with JDTic. Nature Epub doi: 10.1038/nature10939.

  9. 4dkl - Manglik, A., et al. Crystal structure of the mu-opioid receptor bound to a morphinan antagonist. Nature Epub doi: 10.1038/nature10954.

  10. 3v2y - Hanson, M. A., et al. Crystal structure of a lipid G protein-coupled receptor. Science 335, 851-855 (2012).

  11. 4ea3 - Thompson, A. A., et al. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature, in press.

  12. 3sn6 - Rasmussen, S. G. F., et al. Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477, 549-555 (2011).

  13. 2che - Stock, A. M. et al. Structure of the Mg(2+)-bound form of CheY and mechanism of phosphoryl transfer in bacterial chemotaxis. Biochemistry 32, 13375-13380 (1993).

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