Small-molecule antagonists of glucagon receptor (GCGR), a class B G protein-coupled receptor, reduce plasma glucose levels in patients with type 2 diabetes. Jazayeri et al. now report the 2.5 Å structure of human GCGR in complex with the antagonist MK-0893, providing an opportunity for structure-based drug design. MK-0893 binds to a novel allosteric site located outside the seven transmembrane (7TM) helical bundle in a position between TM6 and TM7, which prevents glucagon receptor activation by restricting the outward helical movement of TM6 required for G protein signalling.
References
Jazayeri, A. et al. Extra-helical binding site of a glucagon receptor antagonist. Nature http://dx.doi.org/10.1038/nature17414 (2016)
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Crunkhorn, S. Glucagon receptor antagonist binding site identified. Nat Rev Drug Discov 15, 384 (2016). https://doi.org/10.1038/nrd.2016.100
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DOI: https://doi.org/10.1038/nrd.2016.100
