The mechanism for ligand activation of the GPCR–G protein complex
Abstract
G protein–coupled receptors (GPCRs) activate cellular responses ranging from odorants to neurotransmitters. Binding an agonist leads to activation of a heterotrimeric G protein (GP) that stimulates external signaling. Unfortunately, the mechanism remains unknown. We show for 15 class A GPCRs, including opioids, adrenergics, adenosines, chemokines, muscarinics, cannabinoids, serotonins, and dopamines, that interaction of an inactive GP, including Gs, Gi, Go, G11, and Gq, to the inactive GPCR, containing the intracellular ionic lock between transmembrane (TM) helices 3 and 6, evolves exothermically to form a precoupled GPCR-GP complex with an opened TM3-TM6 and the GP-α5 helix partially inserted into the GPCR but not activated. We show that binding of agonist to this precoupled GPCR-GP complex causes the Gα protein to open into its active form, with the guanosine diphosphate exposed for signaling. This GP-first paradigm provides a strategy for developing selective agonists for GPCRs since it is the pharmacophore for the precoupled GPCR-GP complex that should be used to design drugs.
Additional Information
© 2022 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Contributed by William A. Goddard III; received May 31, 2021; accepted March 24, 2022; reviewed by Marco De Vivo and Kenneth A. Jacobson. Published April 22, 2022. Partial support was provided by NIH (R35HL150807) and gifts to the Materials and Process Simulation Center (MSC). Data Availability: All study data are included in the article and/or SI Appendix. Model structures have been deposited in GitHub (https://github.com/amafi-gpcr/G-protein-first-mechanism-of-activation-for-class-A-GPCRs-PNAS-2022), (31). Author contributions: A.M. and W.A.G. designed research; A.M. performed research; A.M., S.-K.K., and W.A.G. analyzed data; and A.M., S.-K.K., and W.A.G. wrote the paper. Reviewers: M.D.V., Istituto Italiano di Tecnologia; and K.A.J., NIH. The authors declare no competing interest. This article contains supporting information online at http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2110085119/-/DCSupplemental.Attached Files
Published - pnas.2110085119.pdf
Supplemental Material - pnas.2110085119.sapp.pdf
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Additional details
- PMCID
- PMC9170043
- Eprint ID
- 114455
- Resolver ID
- CaltechAUTHORS:20220425-841878300
- R35HL150807
- NIH
- Created
-
2022-04-25Created from EPrint's datestamp field
- Updated
-
2023-07-06Created from EPrint's last_modified field
- Other Numbering System Name
- WAG
- Other Numbering System Identifier
- 1518