{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:30:07Z","timestamp":1787049007154,"version":"build-2736575974"},"reference-count":40,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T00:00:00Z","timestamp":1595894400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T00:00:00Z","timestamp":1595894400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T00:00:00Z","timestamp":1595894400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["11575021"],"award-info":[{"award-number":["11575021"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U1530402"],"award-info":[{"award-number":["U1530402"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["RUI-1904797"],"award-info":[{"award-number":["RUI-1904797"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>G-protein-coupled receptors (GPCRs) transmit signals into the cell in response to ligand binding at its extracellular domain, which is characterized by the coupling of agonist-induced receptor conformational change to guanine nucleotide (GDP) exchange with guanosine triphosphate on a heterotrimeric (\u03b1\u03b2\u03b3) guanine nucleotide-binding protein (G-protein), leading to the activation of the G-protein. The signal transduction mechanisms have been widely researched in vivo and in silico. However, coordinated communication from stimulating ligands to the bound GDP still remains elusive. In the present study, we used microsecond (\u03bcS) molecular dynamic (MD) simulations to directly probe the communication from the \u03b22 adrenergic receptor (\u03b22AR) with an agonist or an antagonist or no ligand to GDP bound to the open conformation of the G\u03b1 protein. Molecular mechanism-general Born surface area calculation results indicated either the agonist or the antagonist destabilized the binding between the receptor and the G-protein but the agonist caused a higher level of destabilization than the antagonist. This is consistent with the role of agonist in the activation of the G-protein. Interestingly, while GDP remained bound with the G\u03b1-protein for the two inactive systems (antagonist-bound and apo form), GDP dissociated from the open conformation of the G\u03b1 protein for the agonist activated system. Data obtained from MD simulations indicated that the receptor and the G\u03b1 subunit play a big role in coordinated communication and nucleotide exchange. Based on residue interaction network analysis, we observed that engagement of agonist-bound \u03b22AR with an \u03b15 helix of G\u03b1 is essential for the GDP release and the residues in the phosphate-binding loop, \u03b11 helix, and \u03b15 helix play very important roles in the GDP release. The insights on GPCR\u2013G-protein communication will facilitate the rational design of agonists and antagonists that target both active and inactive GPCR binding pockets, leading to more precise drugs.<\/jats:p>","DOI":"10.1021\/acs.jcim.0c00432","type":"journal-article","created":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T15:34:55Z","timestamp":1595950495000},"page":"4064-4075","source":"Crossref","is-referenced-by-count":12,"title":["GDP Release from the Open Conformation of G\u03b1\nRequires Allosteric Signaling from the Agonist-Bound Human \u03b22 Adrenergic Receptor"],"prefix":"10.1021","volume":"60","author":[{"given":"Vikash","family":"Kumar","sequence":"first","affiliation":[{"name":"Beijing Computational Science Research Center , , Haidian district, ,","place":["Beijing, China, 100193"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Hoag","sequence":"additional","affiliation":[{"name":"Rowan University , , , ,","place":["Glassboro, New Jersey, United States, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safaa","family":"Sader","sequence":"additional","affiliation":[{"name":"Rowan University , , , ,","place":["Glassboro, New Jersey, United States, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Scorese","sequence":"additional","affiliation":[{"name":"Rowan University , , , ,","place":["Glassboro, New Jersey, United States, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiguang","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Computational Science Research Center , , Haidian district, ,","place":["Beijing, China, 100193"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0176-3873","authenticated-orcid":true,"given":"Chun","family":"Wu","sequence":"additional","affiliation":[{"name":"Rowan University , , , ,","place":["Glassboro, New Jersey, United States, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,7,28]]},"reference":[{"key":"2026081805073222700_cit1","doi-asserted-by":"publisher","first-page":"836","DOI":"10.14348\/molcells.2015.0263","article-title":"Structural\nStudies of G Protein-Coupled\nReceptors","volume":"38","author":"Zhang","year":"2015","journal-title":"Mol. 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Biol."},{"key":"2026081805073222700_cit4","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1007\/s00726-013-1593-y","article-title":"GPCR: G protein\ncomplexes-the fundamental signaling assembly","volume":"45","author":"Jastrzebska","year":"2013","journal-title":"Amino Acids"},{"key":"2026081805073222700_cit5","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/nature10361","article-title":"Crystal structure\nof the \u03b22 adrenergic receptor-Gs protein complex","volume":"477","author":"Rasmussen","year":"2011","journal-title":"Nature"},{"key":"2026081805073222700_cit6","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1038\/nature10488","article-title":"Conformational changes in the G protein\nGs induced by the \u03b22 adrenergic receptor","volume":"477","author":"Chung","year":"2011","journal-title":"Nature"},{"key":"2026081805073222700_cit7","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1126\/science.aaa5264","article-title":"Structural basis\nfor nucleotide exchange\nin heterotrimeric G proteins","volume":"348","author":"Dror","year":"2015","journal-title":"Science"},{"key":"2026081805073222700_cit8","doi-asserted-by":"publisher","first-page":"4310","DOI":"10.1021\/ja077268b","article-title":"Mechanisms of inter-\nand intramolecular communication in GPCRs and G proteins","volume":"130","author":"Raimondi","year":"2008","journal-title":"J. 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Chem."},{"key":"2026081805073222700_cit33","doi-asserted-by":"publisher","DOI":"10.7554\/elife.50279","article-title":"Common activation\nmechanism\nof class A GPCRs","volume":"8","author":"Zhou","year":"2019","journal-title":"eLife"},{"key":"2026081805073222700_cit34","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.jmb.2011.10.015","article-title":"Molecular Dynamics\nSimulations of the Effect of the G-Protein and Diffusible Ligands\non the \u03b22-Adrenergic Receptor","volume":"414","author":"Goetz","year":"2011","journal-title":"J. Mol.\nBiol."},{"key":"2026081805073222700_cit35","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1016\/j.cell.2019.04.021","article-title":"Structural Insights\ninto the Process of GPCR-G Protein Complex Formation","volume":"177","author":"Liu","year":"2019","journal-title":"Cell"},{"key":"2026081805073222700_cit36","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/27831","article-title":"G-protein\ndiseases furnish a model\nfor the turn-on switch","volume":"394","author":"Iiri","year":"1998","journal-title":"Nature"},{"key":"2026081805073222700_cit37","doi-asserted-by":"publisher","first-page":"6150","DOI":"10.1073\/pnas.101136198","article-title":"Mutant G protein subunit activated by G : A model for\nreceptor activation?","volume":"98","author":"Rondard","year":"2001","journal-title":"Proc. Natl. Acad. 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