The G protein-first activation mechanism of opioid receptors by Gi protein and agonists
Abstract
G protein-first mechanism of activation for opioid receptors and their cognate Gi protein. Σ0: In the absence of ligand and Gi protein, the opioid receptors adopt the inactive conformation, featuring a tight hydrogen bond between the cytosolic ends of TM3 and TM6 that keeps the cytoplasmic region tightly closed. Σ1: Before agonist binding, the inactive Gi protein tightly bound to GDP couples to inactive opioid receptor, to form a pre-coupled opioid receptor-Gi (GDP) complex. Σ2: Interactions between inactive opioid receptor and inactive Gi (GDP) leads to breaking the TM3-TM6 hydrogen bond and opening the cytoplasmic region of the receptors to accommodate the Gi protein. As a result, the pre-activated state (Σ2) emerges, which remains at this resting state until an agonist binds the receptor. Σ3′: agonist bound to the pre-activated state induces the Gi (GDP) to be activated. Activation of the Gi protein is associated with a remarkable opening in the cleft between AH and Ras-like domains of Gα, providing an exit path for GDP release or exchange with a GTP. Σ4′: Upon GDP release of exchange, the agonist-opioid receptor-Gi protein evolves to its fully active state.
Additional Information
© The Author(s), 2021. Published by Cambridge University Press. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 30 September 2020. Revised: 30 July 2021. Accepted: 02 August 2021. We thank Dr. Sijia Dong and Dr. Fan Liu for helpful discussions. This project was initiated with support by the GIST-Caltech Collaboration with Prof. Yong-Chul Kim of GIST, Korea. It was completed with support from NIH (R01HL155532). These calculations used the computational resources funded by DURIP (ONR N00014-16-1-2901) and the XSEDE (Extreme Science and Engineering Discovery Environment) supported by National Science Foundation Grant (ACI-1548562).Attached Files
Published - the-g-protein-first-activation-mechanism-of-opioid-receptors-by-gi-protein-and-agonists.pdf
Supplemental Material - S2633289221000077sup001.docx
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Additional details
- Eprint ID
- 111544
- Resolver ID
- CaltechAUTHORS:20211019-181528901
- PMCID
- PMC10392629
- GIST-Caltech Collaboration
- R01HL155532
- NIH
- N00014-16-1-2901
- Office of Naval Research (ONR)
- ACI-1548562
- NSF
- Created
-
2021-10-26Created from EPrint's datestamp field
- Updated
-
2021-11-16Created from EPrint's last_modified field
- Other Numbering System Name
- WAG
- Other Numbering System Identifier
- 1480