Mafi, Amirhossein and Kim, Soo-Kyung and Goddard, William A., III (2021) The G protein-first activation mechanism of opioid receptors by Gi protein and agonists. QRB Discovery, 2 (2021). Art. no. e9. ISSN 2633-2892. doi:10.1017/qrd.2021.7. https://resolver.caltech.edu/CaltechAUTHORS:20211019-181528901
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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.
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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). | ||||||||||
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Issue or Number: | 2021 | ||||||||||
DOI: | 10.1017/qrd.2021.7 | ||||||||||
Record Number: | CaltechAUTHORS:20211019-181528901 | ||||||||||
Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20211019-181528901 | ||||||||||
Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||
ID Code: | 111544 | ||||||||||
Collection: | CaltechAUTHORS | ||||||||||
Deposited By: | Donna Wrublewski | ||||||||||
Deposited On: | 26 Oct 2021 15:29 | ||||||||||
Last Modified: | 16 Nov 2021 19:45 |
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