{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T04:13:42Z","timestamp":1788149622629,"version":"build-2803163510"},"reference-count":159,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit? e della Ricerca","doi-asserted-by":"publisher","award":["E93C22001860006"],"award-info":[{"award-number":["E93C22001860006"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>G protein-coupled receptors (GPCRs) represent the therapeutic targets for an estimated 30\u201340% of marketed drugs. By translating the majority of the GPCR structures from the Protein Data Bank into structure graphs and analyzing over 2 million structural contacts, this study maps the landscape of GPCR classification and function. A minimal subset of just 30 specific contacts is sufficient to define the signatures of distinct receptor classes, subfamilies, types, subtypes, and functional states. These structural signatures successfully assigned classifications to the orphan GPCRs. Upon activation, class A GPCRs undergo the most radical network reorganization of all classes, retaining 0% of their state-specific contacts when transitioning from the inactive to the active state, a stark contrast to the 32\u201350% retention observed in classes B1, C, and F. Despite this complete contact turnover across the 7TM bundle, class A activation remains anchored by a highly conserved core of ten universal network nodes. Analysis of representative shortest communication pathways (metapaths) demonstrates that class A GPCRs rely on these highly conserved nodes to bridge structural communication between the orthosteric ligand-binding pocket and the intracellular G-protein-binding site, regardless of the functional state. Furthermore, these metapaths intersect directly with known allosteric binding sites for small allosteric modulators. G protein binding structurally reorganizes the receptor network, funneling a multitude of potential communication pathways into a few preferential routes. These pathways culminate at the highly conserved arginine residue of the E\/DRY motif that acts as a key mediator of G-protein recognition, while structural divergences at the receptor-G protein interface dictate the distinctive pathways of specific G-protein signaling. The wide analysis was able to capture key aspects of the structural communication within the GPCR superfamily with implications in drug discovery.<\/jats:p>","DOI":"10.1021\/jacsau.6c00851","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:02:27Z","timestamp":1785852147000},"page":"4718-4739","source":"Crossref","is-referenced-by-count":0,"title":["Landscape of G Protein-Coupled\nReceptor Function from\nStructure Networks"],"prefix":"10.1021","volume":"6","author":[{"given":"Sara","family":"Gentile","sequence":"first","affiliation":[{"name":"University of Modena and Reggio Emilia , , via Campi 103 , ,","place":["Modena, Italia, 41125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Felline","sequence":"additional","affiliation":[{"name":"University of Modena and Reggio Emilia , , via Campi 103 , ,","place":["Modena, Italia, 41125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Mazzali","sequence":"additional","affiliation":[{"name":"University of Modena and Reggio Emilia , , via Campi 103 , ,","place":["Modena, Italia, 41125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7620-6895","authenticated-orcid":true,"given":"Francesca","family":"Fanelli","sequence":"additional","affiliation":[{"name":"University of Modena and Reggio Emilia , , via Campi 103 , ,","place":["Modena, Italia, 41125"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"issue":"12","key":"2026083023174692900_cit1","doi-asserted-by":"publisher","first-page":"PR438","DOI":"10.1021\/cr100437t","article-title":"Update 1 of: Computational Modeling Approaches to Structure-Function\nAnalysis of G Protein-Coupled Receptors","volume":"111","author":"Fanelli","year":"2011","journal-title":"Chem.\nRev."},{"key":"2026083023174692900_cit2","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1146\/annurev-pharmtox-032112-135923","article-title":"Structure-function of the G protein-coupled\nreceptor superfamily","volume":"53","author":"Katritch","year":"2013","journal-title":"Annu. 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