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Hitchhiking on the heptahelical highway: structure and function of 7TM receptor complexes

Nature Reviews Molecular Cell Biology volume 17, pages 439–450 (2016)Cite this article

Subjects

Key Points

  • Since 2007, the number of high-resolution studies of seven transmembrane domain (7TM) receptors (including G protein-coupled receptors) has greatly increased, providing new insights into signalling by a formerly intractable family of integral membrane proteins.

  • Although new structures have revealed many important pharmacological details about specific ligand-binding sites in different receptor classes, how signals are transduced by 7TM receptors from their ligand-binding pockets to their cytoplasmic partners remains poorly understood.

  • Structures of the β2-adrenergic receptor in complex with the heterotrimeric G protein Gs, and of rhodopsin in complex with arrestin, along with complementary biophysical studies, provide the most detailed views of how such signalling might occur.

  • Both heterotrimeric G proteins and arrestins, and probably G protein-coupled receptor kinases (GRKs), recognize activated 7TM receptors via a common mechanism involving a structural projection that packs into the cytoplasmic pockets formed on activated receptors. The projection is allosterically coupled to other domains, such that receptor docking translates into functional consequences inside the cell.

  • Interactions with activated receptors seem to involve relatively few specific contacts, which probably explains how a relatively small number of G proteins, arrestins and GRKs can recognize the activated state of hundreds of different 7TM receptors.

Abstract

A revolution in the analysis of seven transmembrane domain (7TM) receptors has provided detailed information about how these physiologically important signalling proteins interact with extracellular cues. However, it has proved much more challenging to understand how 7TM receptors convey information to their principal intracellular targets: heterotrimeric G proteins, G protein-coupled receptor kinases and arrestins. Recent structures now suggest a common mechanism that enables these structurally diverse cytoplasmic proteins to 'hitch a ride' on hundreds of different activated 7TM receptors in order to instigate physiological change.

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Figure 1: Seven transmembrane domain (7TM) receptor families and their ligands.
Figure 2: Extracellular and cytoplasmic pockets of four different seven transmembrane domain (7TM) receptors.
Figure 3: Interactions of heterotrimeric G proteins and arrestins with seven transmembrane domain (7TM) receptors.

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Acknowledgements

Research in the Tesmer laboratory is supported by US National Institutes of Health (NIH) grants HL086865, HL122416 and HL071818, and fellowships from the American Cancer Society and the American Heart Association. The author thanks Mindy Mackey for technical assistance.

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  1. Life Sciences Institute and Departments of Pharmacology and Biological Chemistry, University of Michigan, Ann Arbor, 48109–2216, Michigan, USA

    John J. G. Tesmer

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Supplementary information

Supplementary information S1 (figure)

Number of structures of 7TM transmembrane domains released from the Protein Data Bank per year (138 unique diffraction data sets at the time of writing). (PDF 1116 kb)

Supplementary information S2 (table)

Structures of 7TM receptors deposited in the Protein Data Bank (PDB) as of the end of 2015. (XLS 228 kb)

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DATABASES

Protein Data Bank

Protein Data Bank

1F88

3PQR

2RH1

3SN6

4DKL

5C1M

3UON

4MQT

1AZT

4ZWJ

1CF1

4JQI

Glossary

Allosteric change

An alteration in the structure of a specific region of a protein that results from an event occurring at a remote site.

Transducin

The heterotrimeric G protein (also known as Gt) responsible for the propagation of visual signals from light-activated rhodopsin.

Homologous desensitization

The process by which receptors that recognize a specific agonist or signal become gradually resistant to further stimulation, often by downregulation of the number of receptors on the cell surface through endocytosis.

Clathrin-mediated endocytosis

A process by which membrane proteins are sequestered into distinct regions of the cell membrane, which are then internalized with the help of the protein clathrin to form intracellular vesicles.

Agonists

Molecules that promote a conformation (or an ensemble of conformations) of a receptor that is more capable of binding to and activating a downstream signalling protein.

Biased agonism

A phenomenon in which an agonist (known as a biased agonist) promotes interactions with one downstream signalling partner or cascade over another.

Inverse agonist

A molecule that reduces signalling by a receptor to a level below that observed in its basal, unliganded state.

Antagonist

A molecule that blocks the binding of other molecules to a receptor, but that on its own has little effect on signalling.

Nanobodies

Single-domain, ∼15 kDa fragments produced from single heavy-chain antibodies found in cameloid species (for example, llamas and alpacas). They are now also generated by in vitro methodologies such as directed evolution.

α-helical domain

A helical domain unique to heterotrimeric G proteins, inserted into a loop of the Ras-like domain. It contributes to the rate of GTP hydrolysis and also can modulate interactions between the Ras-like domain of Gα and its signalling partners.

Ras-like domain

The nucleotide-binding domain of heterotrimeric G protein α-subunits, which also contains binding sites for seven transmembrane (7TM) receptors, Gβγ subunits, and downstream effector enzymes. It contains three switch regions that are conformationally responsive to the identity of the bound nucleotide.

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Tesmer, J. Hitchhiking on the heptahelical highway: structure and function of 7TM receptor complexes. Nat Rev Mol Cell Biol 17, 439–450 (2016). https://doi.org/10.1038/nrm.2016.36

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