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dc.contributor.authorWang, Jinan
dc.contributor.authorMiao, Yinglong
dc.date.accessioned2020-03-27T19:15:32Z
dc.date.available2020-03-27T19:15:32Z
dc.date.issued2019-07-08
dc.identifier.citationWang, J., & Miao, Y. (2019). Mechanistic Insights into Specific G Protein Interactions with Adenosine Receptors. The journal of physical chemistry. B, 123(30), 6462–6473. https://doi.org/10.1021/acs.jpcb.9b04867en_US
dc.identifier.urihttp://hdl.handle.net/1808/30197
dc.descriptionThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Physical Chemistry B, copyright © 2019 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jpcb.9b04867.en_US
dc.description.abstractCoupling between G-protein-coupled receptors (GPCRs) and the G proteins is a key step in cellular signaling. Despite extensive experimental and computational studies, the mechanism of specific GPCR–G protein coupling remains poorly understood. This has greatly hindered effective drug design of GPCRs that are primary targets of ∼1/3 of currently marketed drugs. Here, we have employed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method to decipher the mechanism of the GPCR–G protein interactions. Adenosine receptors (ARs) were used as model systems based on very recently determined cryo-EM structures of the A1AR and A2AAR coupled with the Gi and Gs proteins, respectively. Changing the Gi protein to the Gs led to increased fluctuations in the A1AR and agonist adenosine (ADO), while agonist 5′-N-ethylcarboxamidoadenosine (NECA) binding in the A2AAR could be still stabilized upon changing the Gs protein to the Gi. Free energy calculations identified one stable low-energy conformation for each of the A1AR-Gi and A2AAR-Gs complexes as in the cryo-EM structures, similarly for the A2AAR-Gi complex. In contrast, the ADO agonist and Gs protein sampled multiple conformations in the A1AR-Gs system. GaMD simulations thus indicated that the A1AR preferred to couple with the Gi protein to the Gs, while the A2AAR could couple with both the Gs and Gi proteins, being highly consistent with experimental findings of the ARs. More importantly, detailed analysis of the atomic simulations showed that the specific AR-G protein coupling resulted from remarkably complementary residue interactions at the protein interface, involving mainly the receptor transmembrane 6 helix and the Gα α5 helix and α4-β6 loop. In summary, the GaMD simulations have provided unprecedented insights into the dynamic mechanism of specific GPCR–G protein interactions at an atomistic level.en_US
dc.publisherAmerican Chemical Societyen_US
dc.rights© 2019 American Chemical Societyen_US
dc.titleMechanistic Insights into Specific G Protein Interactions with Adenosine Receptorsen_US
dc.typeArticleen_US
kusw.kuauthorWang, Jinan
kusw.kuauthorMiao, Yinglong
kusw.kudepartmentMolecular Biosciencesen_US
dc.identifier.doi10.1021/acs.jpcb.9b04867en_US
dc.identifier.orcidhttps://orcid.org/0000-0003-0162-212Xen_US
dc.identifier.orcidhttps://orcid.org/0000-0003-3714-1395en_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC7026936en_US
dc.rights.accessrightsOpenAccessen_US


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