G protein coupling and activation of the metabotropic GABA₈ heterodimer
Abstract
Metabotropic γ-aminobutyric acid receptor (GABA₈R), a class C G protein-coupled receptor (GPCR) heterodimer, plays a crucial role in the central nervous system. Cryo-electron microscopy studies revealed a drastic conformational change upon activation and a unique G protein (GP) binding mode. However, little is known about the mechanism for GP coupling and activation for class C GPCRs. Here, we use molecular metadynamics computations to predict the mechanism by which the inactive GP induces conformational changes in the GABA₈R transmembrane domain (TMD) to form an intermediate pre-activated state. We find that the inactive GP first interacts with TM3, which further leads to the TMD rearrangement and deeper insertion of the α5 helix that causes the Gα subunit to open, releasing GDP, and forming the experimentally observed activated structure. This mechanism provides fresh insights into the mechanistic details of class C GPCRs activation expected to be useful for designing selective agonists and antagonists.
Additional Information
© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 10 February 2022. Accepted 21 July 2022. Published 08 August 2022. This research was supported by gifts to the MSC with some support from the NIH (R01HL155532). A part of the computational resource was provided by the Anton2 computer at the Pittsburgh National Supercomputing Centre (MCB180091P). Contributions. M.Y.Y. and W.A.G. planned the project, M.Y.Y. carried out all computations. M.Y.Y. wrote the manuscript with help from W.A.G. and S.K.K. All authors approved the final manuscript. Data availability. The main data supporting the findings of this study are available within the article and its Supplementary Information. The cryo-EM and X-ray structures used in this study are available in the Protein Data Bank database under accession codes 7C7Q, 7EB2, 6UO9, and 1GOT. Additional data are available from the corresponding author upon reasonable request. The authors declare no competing interests. Peer review information. Nature Communications thanks Madan Babu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.Attached Files
Published - s41467-022-32213-3.pdf
Supplemental Material - 41467_2022_32213_MOESM1_ESM.pdf
Supplemental Material - 41467_2022_32213_MOESM2_ESM.pdf
Supplemental Material - 41467_2022_32213_MOESM3_ESM.pdf
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Additional details
- PMCID
- PMC9360005
- Eprint ID
- 116159
- Resolver ID
- CaltechAUTHORS:20220808-223815000
- R01HL155532
- NIH
- MCB180091P
- Pittsburgh National Supercomputing Center
- Created
-
2022-08-09Created from EPrint's datestamp field
- Updated
-
2022-08-15Created from EPrint's last_modified field
- Other Numbering System Name
- WAG
- Other Numbering System Identifier
- 1526