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However, previous studies have shown that certain amino acid residue positions that play a critical role in protein function are often in a suboptimal energy state or \u201cfrustrated\u201d. Here, we leverage over 1200 three-dimensional structures of G protein-coupled receptors (GPCRs) to demonstrate that residues at the interface between GPCR and its ligand or G protein contain a higher density of frustrated residues compared to other structural regions in the receptor. Likewise, the G\u03b1 subunit of the trimeric G proteins shows multiple clusters of highly frustrated residues on its surface that overlap with their effector protein (Gb\u03b3, RGS, Adenylyl cyclase, Ric8) binding interfaces. Our study highlights the use of protein frustration as one of the multiple structural properties to identify protein\u2013protein interfaces and for prospective prediction of potential ligand binding sites.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c00203","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T12:19:36Z","timestamp":1783945176000},"page":"8410-8422","source":"Crossref","is-referenced-by-count":0,"title":["Protein Frustration\nReveals Orthosteric and Allosteric\nActive Sites in GPCR:G Protein Complexes"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5146-8048","authenticated-orcid":true,"given":"Wenyuan","family":"Wei","sequence":"first","affiliation":[{"name":"Beckman Research Institute of the City of Hope , , 1218 S 5th Ave , , ,","place":["Monrovia, California, United States, 91016"]},{"name":"Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope , 1500 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91016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9911-7625","authenticated-orcid":true,"given":"Elizaveta","family":"Mukhaleva","sequence":"additional","affiliation":[{"name":"Beckman Research Institute of the City of Hope , , 1218 S 5th Ave , , ,","place":["Monrovia, California, United States, 91016"]},{"name":"Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope , 1500 E Duarte Road , , ,","place":["Duarte, California, United States, 91010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indira R.","family":"Sivaraj","sequence":"additional","affiliation":[{"name":"Beckman Research Institute of the City of Hope , , 1218 S 5th Ave , , ,","place":["Monrovia, California, United States, 91016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0566-6779","authenticated-orcid":true,"given":"Veerabahu","family":"Shanmugasundaram","sequence":"additional","affiliation":[{"name":"Bristol-Myers-Squibb , 250 Water Street , , ,","place":["Cambridge, Massachusetts, United States, 02141"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Branciamore","sequence":"additional","affiliation":[{"name":"Beckman Research Institute of the City of Hope , , 1218 S 5th Ave , , ,","place":["Monrovia, California, United States, 91016"]},{"name":"Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope , 1500 E Duarte Road , , ,","place":["Duarte, California, United States, 91010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei S.","family":"Rodin","sequence":"additional","affiliation":[{"name":"Beckman Research Institute of the City of Hope , , 1218 S 5th Ave , , ,","place":["Monrovia, California, United States, 91016"]},{"name":"Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope , 1500 E Duarte Road , , ,","place":["Duarte, California, United States, 91010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9541-6994","authenticated-orcid":true,"given":"Sivaraj","family":"Sivaramakrishnan","sequence":"additional","affiliation":[{"name":"University of Minnesota , , , ,","place":["Minneapolis, Minnesota, United States, 55455"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4653-7797","authenticated-orcid":true,"given":"Ning","family":"Ma","sequence":"additional","affiliation":[{"name":"Beckman Research Institute of the City of Hope , , 1218 S 5th Ave , , ,","place":["Monrovia, California, United States, 91016"]},{"name":"Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope , 1500 E Duarte Road , , ,","place":["Duarte, California, United States, 91010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8100-8132","authenticated-orcid":true,"given":"Nagarajan","family":"Vaidehi","sequence":"additional","affiliation":[{"name":"Beckman Research Institute of the City of Hope , , 1218 S 5th Ave , , ,","place":["Monrovia, California, United States, 91016"]},{"name":"Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope , 1500 E Duarte Road , , ,","place":["Duarte, California, United States, 91010"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"2026072709082246700_cit1","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.sbi.2017.09.006","article-title":"Frustration, function and 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Preprint at https:\/\/doi.org\/10.1101\/2022.12.11.519349 (2022).","DOI":"10.1101\/2022.12.11.519349"},{"key":"2026072709082246700_cit5","doi-asserted-by":"publisher","first-page":"D1006","DOI":"10.1093\/nar\/gkz951","article-title":"The IUPHAR\/BPS\nGuide to PHARMACOLOGY in 2020: extending immunopharmacology content\nand introducing the IUPHAR\/MMV Guide to MALARIA PHARMACOLOGY","volume":"48","author":"Armstrong","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2026072709082246700_cit6","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/s41392-024-01803-6","article-title":"G protein-coupled\nreceptors (GPCRs): advances in structures, mechanisms and drug discovery","volume":"9","author":"Zhang","year":"2024","journal-title":"Sig Transduct Target Ther"},{"key":"2026072709082246700_cit7","doi-asserted-by":"publisher","first-page":"ra123","DOI":"10.1126\/scisignal.aab4068","article-title":"Distinct profiles\nof functional discrimination among G proteins determine the actions\nof G protein\u2013coupled receptors","volume":"8","author":"Masuho","year":"2015","journal-title":"Sci.\nSignal."},{"key":"2026072709082246700_cit8","doi-asserted-by":"publisher","first-page":"3038","DOI":"10.1093\/bioinformatics\/btab176","article-title":"FrustratometeR:\nan R-package to compute local frustration in protein structures, point\nmutants and MD simulations","volume":"37","author":"Rausch","year":"2021","journal-title":"Bioinformatics"},{"key":"2026072709082246700_cit9","first-page":"366","article-title":"[19]\nIntegrated methods for the construction of three-dimensional models\nand computational probing of structure-function relations in G protein-coupled\nreceptors","volume-title":"Methods in Neurosciences","author":"Ballesteros","year":"1995"},{"key":"2026072709082246700_cit10","doi-asserted-by":"publisher","first-page":"5211","DOI":"10.1073\/pnas.1221585110","article-title":"Polar transmembrane interactions drive formation of\nligand-specific and signal pathway-biased family B G protein-coupled\nreceptor conformations","volume":"110","author":"Wootten","year":"2013","journal-title":"Proc. Natl. Acad. Sci.\nU.S.A."},{"key":"2026072709082246700_cit11","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/S0163-7258(03)00038-X","article-title":"Evolution, structure, and activation\nmechanism of family 3\/C G-protein-coupled receptors","volume":"98","author":"Pin","year":"2003","journal-title":"Pharmacol Ther"},{"key":"2026072709082246700_cit12","doi-asserted-by":"publisher","first-page":"4355","DOI":"10.1038\/ncomms5355","article-title":"Structural\nbasis for Smoothened receptor modulation and chemoresistance to anticancer\ndrugs","volume":"5","author":"Wang","year":"2014","journal-title":"Nat. Commun."},{"key":"2026072709082246700_cit13","doi-asserted-by":"publisher","first-page":"eadf2173","DOI":"10.1126\/scisignal.adf2173","article-title":"Unraveling\nallostery within the angiotensin II type 1 receptor for G\u03b1q\nand \u03b2-arrestin coupling","volume":"16","author":"Cao","year":"2023","journal-title":"Sci. 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Biol."},{"key":"2026072709082246700_cit17","doi-asserted-by":"publisher","first-page":"10744","DOI":"10.1073\/pnas.0804396105","article-title":"Co-evolving stability\nand conformational homogeneity of the human adenosine A2a receptor","volume":"105","author":"Magnani","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026072709082246700_cit18","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.jmb.2009.04.068","article-title":"Thermostabilization\nof the neurotensin receptor NTS1","volume":"390","author":"Shibata","year":"2009","journal-title":"J. Mol. Biol."},{"key":"2026072709082246700_cit19","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.1016\/j.str.2013.09.020","article-title":"The role of\na sodium ion binding site in the allosteric modulation of the A(2A)\nadenosine G protein-coupled receptor","volume":"21","author":"Gutie\u0301rrez-de-Tera\u0301n","year":"2013","journal-title":"Structure"},{"key":"2026072709082246700_cit20","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3389\/fendo.2017.00061","article-title":"Distinct Conformational\nDynamics of Three G Protein-Coupled Receptors Measured Using FlAsH-BRET\nBiosensors","volume":"8","author":"Bourque","year":"2017","journal-title":"Front. Endocrinol."},{"key":"2026072709082246700_cit21","doi-asserted-by":"publisher","first-page":"5944","DOI":"10.1038\/s41467-020-19560-9","article-title":"Surveying\nbiomolecular frustration at atomic resolution","volume":"11","author":"Chen","year":"2020","journal-title":"Nat. Commun."},{"key":"2026072709082246700_cit22","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/nature10361","article-title":"Crystal\nstructure of the \u03b22 adrenergic receptor-Gs protein complex","volume":"477","author":"Rasmussen","year":"2011","journal-title":"Nature"},{"key":"2026072709082246700_cit23","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1038\/s41467-023-37233-1","article-title":"Function and\ndynamics of the intrinsically disordered carboxyl terminus of \u03b22\nadrenergic receptor","volume":"14","author":"Heng","year":"2023","journal-title":"Nat. Commun."},{"key":"2026072709082246700_cit24","doi-asserted-by":"publisher","first-page":"5784","DOI":"10.1038\/s41467-019-13722-0","article-title":"Helix 8 is\nthe essential structural motif of mechanosensitive GPCRs","volume":"10","author":"Erdogmus","year":"2019","journal-title":"Nat. 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Endocrinol."},{"key":"2026072709082246700_cit26","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1038\/s41586-020-2994-1","article-title":"Structure\nof the class D GPCR Ste2 dimer coupled to two G proteins","volume":"589","author":"Velazhahan","year":"2021","journal-title":"Nature"},{"key":"2026072709082246700_cit27","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/S0014-5793(96)01214-8","article-title":"The isolated\nN-terminal extracellular\ndomain of the glucagon-like peptide-1 (GLP)-1 receptor has intrinsic\nbinding activity","volume":"398","author":"Wilmen","year":"1996","journal-title":"FEBS Lett."},{"key":"2026072709082246700_cit28","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1146\/annurev.pharmtox.011008.145533","article-title":"Metabotropic Glutamate\nReceptors: Physiology, Pharmacology,\nand Disease","volume":"50","author":"Niswender","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"2026072709082246700_cit29","doi-asserted-by":"publisher","first-page":"1967","DOI":"10.1038\/s41467-017-01489-1","article-title":"Allosteric\nnanobodies uncover a role of hippocampal mGlu2 receptor homodimers\nin contextual fear consolidation","volume":"8","author":"Scholler","year":"2017","journal-title":"Nat. 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Natl. Acad. Sci. U.S.A."},{"key":"2026072709082246700_cit34","doi-asserted-by":"publisher","first-page":"107362","DOI":"10.1016\/j.jbc.2024.107362","article-title":"Bayesian network\nmodels identify cooperative GPCR:G protein interactions that contribute\nto G protein coupling","volume":"300","author":"Mukhaleva","year":"2024","journal-title":"J. Biol. Chem."},{"key":"2026072709082246700_cit35","doi-asserted-by":"publisher","first-page":"e2017201118","DOI":"10.1073\/pnas.2017201118","article-title":"\u03b22-adrenoceptor\nligand efficacy is tuned by a two-stage interaction with the G\u03b1s\nC terminus","volume":"118","author":"Kim","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026072709082246700_cit36","doi-asserted-by":"publisher","first-page":"12054","DOI":"10.1073\/pnas.1905993116","article-title":"Variable G\nprotein determinants of GPCR coupling selectivity","volume":"116","author":"Okashah","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026072709082246700_cit37","doi-asserted-by":"publisher","first-page":"7428","DOI":"10.1038\/s41467-022-34055-5","article-title":"Dynamic spatiotemporal\ndeterminants modulate GPCR:G protein coupling selectivity and promiscuity","volume":"13","author":"Sandhu","year":"2022","journal-title":"Nat. Commun."},{"key":"2026072709082246700_cit38","doi-asserted-by":"publisher","first-page":"17929","DOI":"10.1074\/jbc.M116.735720","article-title":"Structural\nElements in the G\u03b1s and G\u03b1q C Termini That Mediate Selective\nG Protein-coupled Receptor (GPCR) Signaling","volume":"291","author":"Semack","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2026072709082246700_cit39","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1038\/s41586-024-07153-1","article-title":"Time-resolved\ncryo-EM of G-protein activation by a GPCR","volume":"629","author":"Papasergi-Scott","year":"2024","journal-title":"Nature"},{"key":"2026072709082246700_cit40","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1126\/science.aaa5264","article-title":"SIGNAL\nTRANSDUCTION. Structural basis for nucleotide exchange in heterotrimeric\nG proteins","volume":"348","author":"Dror","year":"2015","journal-title":"Science"},{"key":"2026072709082246700_cit41","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1016\/j.molcel.2021.02.002","article-title":"A universal\nallosteric mechanism for G protein activation","volume":"81","author":"Knight","year":"2021","journal-title":"Mol. 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Signal."},{"key":"2026072709082246700_cit43","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1186\/1471-2105-10-168","article-title":"Fpocket: an open source\nplatform for ligand pocket detection","volume":"10","author":"Le Guilloux","year":"2009","journal-title":"BMC Bioinformatics"},{"key":"2026072709082246700_cit44","doi-asserted-by":"publisher","first-page":"e73901","DOI":"10.7554\/eLife.73901","article-title":"Allosteric\nmodulation of the adenosine A2A receptor by cholesterol","volume":"11","author":"Huang","year":"2022","journal-title":"eLife"}],"container-title":["Journal of Chemical Information\nand Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.6c00203","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/14\/8410\/65889788\/acs.jcim.6c00203.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/14\/8410\/65889788\/acs.jcim.6c00203.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T13:32:38Z","timestamp":1785159158000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/66\/14\/8410\/5207339\/Protein-Frustration-Reveals-Orthosteric-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":44,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7,13]]},"published-print":{"date-parts":[[2026,7,27]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.6c00203","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]}}}