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The second extracellular loop: a damper for G protein–coupled receptors?

Nature Structural & Molecular Biology volume 12, pages 287–288 (2005)Cite this article

A recent study suggests a novel role for the second extracellular loop of GPCRs: it may orchestrate a network of interactions that stabilize the inactive conformation of the receptor and control the on-off transition.

The overall structure and positioning of EC2 within the receptor structure is known for rhodopsin only. In the crystal structure of its inactive form, this region adopts an antiparallel β-hairpin structure and forms a lid on top of the retinal4. A recent study of the dopamine D2 receptor based on the substituted-cysteine accessibility method provides the only other evidence for the positioning of EC2 within the GPCR binding crevice5. The pattern of accessibility obtained for the mutated residues is consistent with a structure similar to that of rhodopsin, in which EC2 is folded down between TMs IV and V (Fig. 1). One salient feature of EC2 is a cysteine residue conserved in nearly all GPCRs. This cysteine is believed to form a disulfide bridge with an equally well-conserved cysteine residue in TM III, helping to constrain EC2 toward the helical core6, although the existence of a disulfide bridge has been verified in only some GPCRs7.

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Figure 1: The second extracellular loop (EC2) in GPCRs.

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  1. IGBMC, CNRS/INSERM/ULP, 1 rue Laurent Fries BP 10142, Illkirch, 67404, Cedex, France

    Dominique Massotte & Brigitte L Kieffer

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  1. Dominique Massotte
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  2. Brigitte L Kieffer
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Massotte, D., Kieffer, B. The second extracellular loop: a damper for G protein–coupled receptors?. Nat Struct Mol Biol 12, 287–288 (2005). https://doi.org/10.1038/nsmb0405-287

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