Dynamic allosteric networks drive adenosine A1 receptor activation and G-protein coupling
G-protein coupled receptors (GPCRs) present specific activation pathways and signaling among receptor subtypes. Hence, an extensive knowledge of the structural dynamics of the receptor is critical for the development of therapeutics. Here, we target the adenosine A1 receptor (A1R), for which a negli...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/90773 |
| _version_ | 1797691185490296832 |
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| author | Miguel A Maria-Solano Sun Choi |
| author_facet | Miguel A Maria-Solano Sun Choi |
| author_sort | Miguel A Maria-Solano |
| collection | DOAJ |
| description | G-protein coupled receptors (GPCRs) present specific activation pathways and signaling among receptor subtypes. Hence, an extensive knowledge of the structural dynamics of the receptor is critical for the development of therapeutics. Here, we target the adenosine A1 receptor (A1R), for which a negligible number of drugs have been approved. We combine molecular dynamics simulations, enhanced sampling techniques, network theory, and pocket detection to decipher the activation pathway of A1R, decode the allosteric networks, and identify transient pockets. The A1R activation pathway reveals hidden intermediate and pre-active states together with the inactive and fully-active states observed experimentally. The protein energy networks computed throughout these conformational states successfully unravel the extra and intracellular allosteric centers and the communication pathways that couple them. We observe that the allosteric networks are dynamic, being increased along activation and fine-tuned in the presence of the trimeric G-proteins. Overlap of transient pockets and energy networks uncovers how the allosteric coupling between pockets and distinct functional regions of the receptor is altered along activation. Through an in-depth analysis of the bridge between the activation pathway, energy networks, and transient pockets, we provide a further understanding of A1R. This information can be useful to ease the design of allosteric modulators for A1R. |
| first_indexed | 2024-03-12T02:09:43Z |
| format | Article |
| id | doaj.art-f81c9cc2f0d34c25af93e770099bb800 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T02:09:43Z |
| publishDate | 2023-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-f81c9cc2f0d34c25af93e770099bb8002023-09-06T15:05:47ZengeLife Sciences Publications LtdeLife2050-084X2023-09-011210.7554/eLife.90773Dynamic allosteric networks drive adenosine A1 receptor activation and G-protein couplingMiguel A Maria-Solano0https://orcid.org/0000-0002-7837-0429Sun Choi1https://orcid.org/0000-0002-7669-7954Global AI Drug Discovery Center, College of Pharmacy and Graduate School of Pharmaceutical Science, Ewha Womans University, Seoul, Republic of KoreaGlobal AI Drug Discovery Center, College of Pharmacy and Graduate School of Pharmaceutical Science, Ewha Womans University, Seoul, Republic of KoreaG-protein coupled receptors (GPCRs) present specific activation pathways and signaling among receptor subtypes. Hence, an extensive knowledge of the structural dynamics of the receptor is critical for the development of therapeutics. Here, we target the adenosine A1 receptor (A1R), for which a negligible number of drugs have been approved. We combine molecular dynamics simulations, enhanced sampling techniques, network theory, and pocket detection to decipher the activation pathway of A1R, decode the allosteric networks, and identify transient pockets. The A1R activation pathway reveals hidden intermediate and pre-active states together with the inactive and fully-active states observed experimentally. The protein energy networks computed throughout these conformational states successfully unravel the extra and intracellular allosteric centers and the communication pathways that couple them. We observe that the allosteric networks are dynamic, being increased along activation and fine-tuned in the presence of the trimeric G-proteins. Overlap of transient pockets and energy networks uncovers how the allosteric coupling between pockets and distinct functional regions of the receptor is altered along activation. Through an in-depth analysis of the bridge between the activation pathway, energy networks, and transient pockets, we provide a further understanding of A1R. This information can be useful to ease the design of allosteric modulators for A1R.https://elifesciences.org/articles/90773adenosine A1 receptoractivation pathwayenergy networkstransient pocketsallosteric modulators |
| spellingShingle | Miguel A Maria-Solano Sun Choi Dynamic allosteric networks drive adenosine A1 receptor activation and G-protein coupling eLife adenosine A1 receptor activation pathway energy networks transient pockets allosteric modulators |
| title | Dynamic allosteric networks drive adenosine A1 receptor activation and G-protein coupling |
| title_full | Dynamic allosteric networks drive adenosine A1 receptor activation and G-protein coupling |
| title_fullStr | Dynamic allosteric networks drive adenosine A1 receptor activation and G-protein coupling |
| title_full_unstemmed | Dynamic allosteric networks drive adenosine A1 receptor activation and G-protein coupling |
| title_short | Dynamic allosteric networks drive adenosine A1 receptor activation and G-protein coupling |
| title_sort | dynamic allosteric networks drive adenosine a1 receptor activation and g protein coupling |
| topic | adenosine A1 receptor activation pathway energy networks transient pockets allosteric modulators |
| url | https://elifesciences.org/articles/90773 |
| work_keys_str_mv | AT miguelamariasolano dynamicallostericnetworksdriveadenosinea1receptoractivationandgproteincoupling AT sunchoi dynamicallostericnetworksdriveadenosinea1receptoractivationandgproteincoupling |