Featured System - April 2014
Short description: PSI researchers have solved the structures of a GPCR that binds to peptide hormones, revealing new modes of GPCR recognition.
GPCRs (G protein-coupled receptors) come in many sizes and shapes, each recognizing its own type of signaling molecule. PSI researchers at the GPCR Network have recently determined the structure of the signature seven-helix bundle of the glucagon receptor, revealing the atomic details of a class of GPCRs that recognize short peptide hormones. This structure, along with the related structure of the corticotropin-releasing factor receptor 1, show that "class B" GPCRs have similarities and differences from their GPCR cousins.
Class B GPCRs have a characteristic structure composed of two connected domains. They include a transmembrane domain (in turquoise here) that is similar to other GPCRs, forming a bundle of alpha helices that link binding of the hormone (in pink) to activation of a G-protein inside the cell. An additional domain (in darker blue) is attached on the outer side of the receptor. The peptide hormone is thought to be captured first by this extracellular domain and then delivered to the transmembrane domain.
These receptors are quite flexible and have posed great challenges for structural determination. Researchers have taken a divide-and-conquer approach, breaking the receptor into manageable pieces for structural analysis. Many structures have been obtained for the extracellular domains, on their own and bound to their peptide hormones. Structures for the transmembrane domain have been more elusive, and two structures have only recently been reported to complete our picture of the class B GPCRs: the glucagon receptor (PDB entry 4l6r) and and the corticotropin-releasing factor receptor 1 (PDB entry 4k5y). The illustration shows a model of the full-length complex of the glucagon receptor with glucagon, created by PSI researchers based on conformational modeling, crosslinking, and mutational data.
Structural analogues of the peptide hormones are being used to modify the action of these receptors, for use in the treatment of diabetes and other disorders. The structure on the left shows glucagon-like-peptide-1 (in pink) bound to the extracellular domain of its receptor (blue) (PDB entry 3iol). As with glucagon and its receptor, the hormone forms a short alpha helix that presumably spans between the two domains of the receptor. Exendin-4, a short peptide discovered in the saliva of the Gila monster, also binds to this receptor, having a similar affect on the release of insulin. However, it has several features, such as a tryptophan that forms a compact "cage" structure (seen here near the top), that together stabilize the formation of the active alpha helix (PDB entry 1jrj).
As with the other recent structures of GPCRs, researchers used protein engineering to determine the structures of these elusive subjects. The extracellular domains were removed, and another small, stable protein was inserted in the chain, forming a convenient handle to assist crystallization. The structures of two class B GPCRs (PDB entries 4l6r and 4k5y, shown at left and center) have the familiar bundle of alpha helices spanning the membrane, but showed that the helices are splayed open to create a large binding site for the peptide hormone. To compare these two new structures with a class A receptor (PDB entry 2rh1, shown on the right), the JSmol tab below displays an interactive JSmol.
The transmembrane domains of two class B GPCRs are overlapped here, along with one class A GPCR. Notice that the helices are splayed open in the class B receptors to create a large binding site for the peptide hormones.
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