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The G protein-first activation mechanism of opioid receptors by Gi protein and agonists

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.

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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.

Item Type:Article
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URLURL TypeDescription
Mafi, Amirhossein0000-0002-8366-6785
Kim, Soo-Kyung0000-0002-4498-5441
Goddard, William A., III0000-0003-0097-5716
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 (, 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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GIST-Caltech CollaborationUNSPECIFIED
Office of Naval Research (ONR)N00014-16-1-2901
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Issue or Number:2021
Record Number:CaltechAUTHORS:20211019-181528901
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ID Code:111544
Deposited By: Donna Wrublewski
Deposited On:26 Oct 2021 15:29
Last Modified:16 Nov 2021 19:45

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