Hot topics: Crystal structure of full-length glucagon receptor provides insight into relative orientation of extracellular and transmembrane domains in an inactive conformation and importance of dynamic changes in this orientation for activation

It has been quite challenging to gain high resolution structural insights into an intact class B G protein-coupled receptor, despite previous solution of multiple structures for the two dominant domains, the extracellular domain (ECD) and the transmembrane helical bundle domain (TMD) of this family of receptors. Zhang et al. (1) now report a crystal structure of full length glucagon receptor (GCGR) in an inactive conformation stabilized by the non-peptidyl antagonist, NNC0640, and mAb1, bound to the ECD. In this new structure, the ECD is elongated above the TMD, with mAb1 resting on extracellular loop 1 (ECL1), and with the stalk region that links the two dominant receptor domains present in a β-strand conformation lying across the helical bundle between ECL1 and ECL2/ECL3. Of particular interest, hydrogen bonds are formed between the stalk and ECL1 to establish a compact β-sheet. The conformation of the stalk in this structure is different from the α-helical extension of TM1 present in the previous solved structure of the isolated ECD of this receptor (2), with the orientation of the ECD in the new structure quite different from that previously predicted. The authors used data from hydrogen-deuterium exchange, disulfide crosslinking, and molecular dynamics to suggest that the relatively stable β-sheet formed by the stalk and ECL1 plays an important role in controlling accessibility of the orthosteric peptide ligand to its site of docking and in the transition of inactive to active receptor states. A hypothetical model is proposed whereby the C-terminus of glucagon gains access to the peptide-binding groove within the ECD, a step that requires ECD separation from the stalk/ECL1 complex, with this initial ligand-binding event leading to a conformational change in the receptor that is not yet understood, allowing the N-terminus of glucagon to dock within the TMD to activate the receptor. A recent report of the use of cryo-EM to determine the structure of another member of the class B family, the calcitonin receptor, in active conformation in complex with salmon calcitonin and its heterotrimeric G protein (3), also emphasizes the relative mobility of ECD and TMD, and the importance of dynamic changes in orientation of these domains. It will be important to gain more insights into the structure and conformational flexibility of apo-receptors in this family to better understand how the natural peptide ligands gain access to the ECD, and to learn more about other possible sites of contact between ECD and TMD that could contribute to conformational changes in the TMD. These reports emphasize the functional importance and likely variations that will exist in the relative orientations of these key structural domains for this class of GPCRs.

[1] Zhang et al. (2017). Structure of the full-length glucagon class B G-protein-coupled receptor. Nature, doi:10.1038/nature222363. [PMID: 28514451]
[2] Siu et al. (2013). Structure of the human glucagon class B G-protein-coupled receptor. Nature, 488:444-449. [PMID: 23863937]
[3] Liang et al. (2017). Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature,doi: 10.1038/nature22327. [Epub ahead of print] [PMID: 28437792]

Comments by Laurence J. Miller (Mayo Clinic, Scottsdale, AZ, USA)

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