The glucagon-like peptide-1 receptor (GLP-1R) is a major target for treatment of Type 2 diabetes but has been refractory to the development of small molecule compounds as potential therapeutics. Song et al., (1) report the first crystal structures of the GLP-1R transmembrane domain in complex with 2 distinct negative allosteric modulators (NAMs) (PF-06372222 and NNC0640). The work provides insight into inactive state structure for the GLP-1R and key interactions that drive inhibitor potency. Moreover, the work allows modelling of an allosteric agonist (and positive allosteric modulator, PAM), Novo Nordisk compound 2, to reveal a potential mechanism for allosteric receptor activation that is supported by mutagenesis and molecular dynamics simulations. The proposed mechanism would lead to a decreased energy barrier for receptor activation through reorganisation of hydrogen bond networks at the base of the receptor that are important for receptor quiescence, and is consistent with the known pharmacology of the PAM in modulating orthosteric peptide activation of the receptor. This work, combined with novel structures of active class B receptors, opens up new possibilities for design of small molecule compounds to manipulate receptor pharmacology and as potential therapeutic drug leads.
[1] Song et al. (2017) Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature, doi:10.1038/nature22378. [PMID 28514449]
Comments by Patrick Sexton (Monash Univeristy, Melbourne)
guidetopharmacology blog 
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