Universal activation mechanism of class A GPCRs

Zhao, S.; Wang, M.-W.; Babu, M.; Stevens, R. C.; Liu, Z.-J.; Shakhnovich, E. I.; Dai, A.; Cai, X.; Zhong, L.; Guo, W.; Guo, Y.; Wu, M.; Yang, D.; Zhou, Q.

doi:10.1101/710673

bioRxiv · 10.1101/710673

Universal activation mechanism of class A GPCRs

Zhao, S.·Wang, M.-W.·Babu, M.·Stevens, R. C.·Liu, Z.-J.·Shakhnovich, E. I.·Dai, A.·Cai, X.·Zhong, L.·Guo, W.·Guo, Y.·Wu, M.·Yang, D.·Zhou, Q.

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Abstract

Class A G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. GPCR activation is an allosteric process that links agonist binding to G protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue-level changes of this trigger remain less well understood. Here, by analyzing over 230 high-resolution structures of class A GPCRs, we discovered a modular, universal GPCR activation pathway that unites previous findings into a common activation mechanism, directly linking the bottom of ligand-binding pocket with G protein-coupling region. We suggest that the modular nature of the universal GPCR activation pathway allowed for the decoupling of the evolution of the ligand binding site, G protein binding region and the residues important for receptor activation. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature.

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Zhao, S., Wang, M.-W., Babu, M., Stevens, R. C., Liu, Z.-J., Shakhnovich, E. I., Dai, A., Cai, X., Zhong, L., Guo, W., Guo, Y., Wu, M., Yang, D., Zhou, Q.. 2019-07-22. Universal activation mechanism of class A GPCRs. https://doi.org/10.1101/710673

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