Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

Cong, Z.; Chen, L.-N.; Ma, H.; Zhou, Q.; Zou, X.; Ye, C.; Dai, A.; Liu, Q.; Huang, W.; Sun, X.; Wang, X.; Xu, P.; Zhao, L.; Xia, T.; Zhong, W.; Yang, D.; Xu, H. E.; Zhang, Y.; Wang, M.-W.

doi:10.1101/2021.05.29.446269

bioRxiv · 10.1101/2021.05.29.446269

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

Cong, Z.·Chen, L.-N.·Ma, H.·Zhou, Q.·Zou, X.·Ye, C.·Dai, A.·Liu, Q.·Huang, W.·Sun, X.·Wang, X.·Xu, P.·Zhao, L.·Xia, T.·Zhong, W.·Yang, D.·Xu, H. E.·Zhang, Y.·Wang, M.-W.

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Abstract

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer the structural basis of ago-allosterism at GLP-1R and new knowledge to design better therapeutics.

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Cong, Z., Chen, L.-N., Ma, H., Zhou, Q., Zou, X., Ye, C., Dai, A., Liu, Q., Huang, W., Sun, X., Wang, X., Xu, P., Zhao, L., Xia, T., Zhong, W., Yang, D., Xu, H. E., Zhang, Y., Wang, M.-W.. 2021-05-29. Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor. https://doi.org/10.1101/2021.05.29.446269

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