Heifetz, A;
Morao, I;
Babu, MM;
James, T;
Southey, MWY;
Fedorov, DG;
Aldeghi, M;
... Townsend-Nicholson, A; + view all
(2020)
Characterising Inter-helical Interactions of G Protein-Coupled Receptors with the Fragment Molecular Orbital Method.
Journal of Chemical Theory and Computation
10.1021/acs.jctc.9b01136.
(In press).
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Abstract
G-protein coupled receptors (GPCRs) are the largest superfamily of membrane proteins, regulating almost every aspect of cellular activity and serving as key targets for drug discovery. We have identified an accurate and reliable computational method to characterise the strength and chemical nature of the inter-helical interactions between the residues of transmembrane (TM) domains during different receptor activation states, something that cannot be characterised solely by visual inspection of structural information. Using the fragment molecular orbital (FMO) quantum mechanics method to analyse 35 crystal structures representing different branches of the class A GPCR family, we have identified 69 topologically-equivalent TM residues that form a consensus network of 51 inter-TM interactions, providing novel results that are consistent with and help to rationalise experimental data. This discovery establishes a comprehensive picture of how defined molecular forces govern specific inter-helical interactions which, in turn, support the structural stability, ligand binding and activation of GPCRs.
| Type: | Article |
|---|---|
| Title: | Characterising Inter-helical Interactions of G Protein-Coupled Receptors with the Fragment Molecular Orbital Method |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acs.jctc.9b01136 |
| Publisher version: | https://doi.org/10.1021/acs.jctc.9b01136 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10092459 |
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