{"database":"BioModels","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Xml":["https://www.ebi.ac.uk/biomodels/model/download/MODEL2306220001?filename=Single_G_protein_Model.xml"],"Other":["https://www.ebi.ac.uk/biomodels/model/download/MODEL2306220001?filename=Single_G_protein_Model.cps"]},"type":"primary"},"statusCodeValue":200,"statusCode":"OK"}],"scores":null,"additional":{"submitter":["Theo Redfern-Nichols"],"curationStatus":["Non-curated"],"modellingApproach":["ordinary differential equation model"],"levelVersion":["L3V1"],"full_dataset_link":["https://www.ebi.ac.uk/biomodels/MODEL2306220001"],"publication_pubmed":["40392940"],"isPrivate":["false"],"repository":["BioModels"],"modelFormat":["SBML"],"omics_type":["Models"],"tokenised_name":["GPCR Cubic Ternary Complex with G protein Cycle, Redfern Nichols 2023"],"publication_year":["2025"],"submissionId":["MODEL2306220001"],"publication_authors":["Theo Redfern-Nichols, Shannon L O'Brien, Xianglin Huang, Brian Medel-Lacruz, Davide Calebiro, Jana Selent, Graham Ladds, Maria Marti-Solano"],"first_author":["Theo Redfern-Nichols"],"publication":["40392940,\n                            G protein-coupled receptors (GPCRs) are transmembrane detectors of extracellular signals that activate heterotrimeric G proteins to regulate intracellular responses. Because there are only 16 Gα proteins that can couple to GPCRs, variation in a single Gα can affect the function of numerous receptors. Here, we investigated two mutant forms of Gαs (L388R and E392K) that are associated with pseudohypoparathyroidism type Ic (PHPIc), a maternally inherited rare disease. Gαs is encoded by an imprinted gene, resulting in the mutant form of Gαs being the only version of the protein present in certain tissues, which leads to tissue-specific disease manifestations. By integrating data from three-dimensional structures, GPCR-G protein coupling specificity, transcriptomics, biophysics, and molecular dynamics with systems pharmacology modeling, we identified GPCRs whose signaling could be altered by Gαs mutations in the kidney, a tissue involved in the pathophysiology of PHPIc. Analysis of G protein activation by the parathyroid hormone receptor 1 (PTH1R) revealed that L388R impaired Gαs interaction with the receptor, whereas E392K reduced the receptor-induced activation of heterotrimeric Gs. This indicates that different signal transduction steps can be altered by specific Gαs mutants associated with the same disease. These findings highlight the importance of investigating mutation-specific perturbations in GPCR signaling to suggest patient-specific treatment strategies. Furthermore, our methods provide a blueprint for interrogating GPCR signaling diversity in different physiological and pathophysiological contexts.. 887, 18.\n                            Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK."],"submitter_mail":["tr428@cam.ac.uk"],"submitter_affiliation":["Department of Pharmacology, University of Cambridge"],"pubmed_abstract":["G protein-coupled receptors (GPCRs) are transmembrane detectors of extracellular signals that activate heterotrimeric G proteins to regulate intracellular responses. Because there are only 16 Gα proteins that can couple to GPCRs, variation in a single Gα can affect the function of numerous receptors. Here, we investigated two mutant forms of Gα<sub>s</sub> (L388R and E392K) that are associated with pseudohypoparathyroidism type Ic (PHPIc), a maternally inherited rare disease. Gα<sub>s</sub> is encoded by an imprinted gene, resulting in the mutant form of Gα<sub>s</sub> being the only version of the protein present in certain tissues, which leads to tissue-specific disease manifestations. By integrating data from three-dimensional structures, GPCR-G protein coupling specificity, transcriptomics, biophysics, and molecular dynamics with systems pharmacology modeling, we identified GPCRs whose signaling could be altered by Gα<sub>s</sub> mutations in the kidney, a tissue involved in the pathophysiology of PHPIc. Analysis of G protein activation by the parathyroid hormone receptor 1 (PTH1R) revealed that L388R impaired Gα<sub>s</sub> interaction with the receptor, whereas E392K reduced the receptor-induced activation of heterotrimeric G<sub>s</sub>. This indicates that different signal transduction steps can be altered by specific Gα<sub>s</sub> mutants associated with the same disease. These findings highlight the importance of investigating mutation-specific perturbations in GPCR signaling to suggest patient-specific treatment strategies. Furthermore, our methods provide a blueprint for interrogating GPCR signaling diversity in different physiological and pathophysiological contexts."],"pubmed_title":["Loss-of-function Gα&lt;sub&gt;s&lt;/sub&gt; rare disease variants exert mutation-specific effects on GPCR signaling."],"pubmed_authors":["Redfern-Nichols Theo T, O'Brien Shannon L SL, Huang Xianglin X, Medel-Lacruz Brian B, Calebiro Davide D, Selent Jana J, Ladds Graham G, Marti-Solano Maria M"],"pubmed_abstract_synonyms":["Forms, Networks, F14G24.19, PTH Related Protein Receptor, Pseudohypoparathyroidisms, Signal Transductions, Albright, nucleocytoplasm, Inheritance, Materials, Pthr, GTP Binding Protein, determination, GTP-Regulatory Proteins, F14G24_19, A4, Parathyroid Hormone Receptor Type 1, PHD Ib, PHD1b, Parathyroid Hormone-Like Peptide, protein, Systematic Pharmacology, Type Ia Pseudohypoparathyroidisms, PHPIa, \"Pseudo-hypoparathyroidism\" EXACT [SNOMEDCT_2005_07_31:154697005], Parathyroid Hormone-Like Peptide Receptor, Molecular Dynamic, Heterotrimeric GTP Binding Protein, Heterotrimeric GTP-Binding, SUB, Mutations, Transcript Expression Analysis, Receptor Mediated Signal Transduction, Inherited, protein polypeptide chains, Techniques, diseases, DmelCG12298, Parathyroid Hormone Receptor Type I, PTHR, Method, Dynamics Simulation, Gene Expression Monitorings, symptoms, PTH-PTHrP Receptor, SCRAMBLED, diseases and disorders, GTP-Binding Protein, Parathyroid Hormone Related Peptide Receptor, Analysis, Profilings, protein aggregate, Cell Signaling, Heterotrimeric G Protein, Effect, KIF20A, \"Albright hereditary osteodystrophy -RETIRED-\" EXACT [SNOMEDCT_2005_07_31:123057000], CD344, signal transduction by protein phosphorylation, treatment, Molecular Dynamics, human disease, VTS20631, Analyses, Dm-OAMB, Molecular, Moods, membrane region, Tissue, hypoplasia, GALR4, PPR, Pathways, proteins, procedures, Gene Expression Analysis, hFz4, Methodological Studies, \"Pseudohypoparathyroidism (disorder)\" EXACT [SNOMEDCT_2005_07_31:58976002], GALRL, disease management, Therapies, Homo sapiens disease, Signal Transduction Pathways, Systematic, Transductions, PGR7, Albright Hereditary Osteodystrophy, intracellular, single organism signaling, CG3856, reniculate kidney, PTH Related Peptide Receptor, Therapy, screening, \"Pseudohypoparathyroidism type Ia\" EXACT [SNOMEDCT_2005_07_31:278716000], GTP Regulatory Protein, GTP Binding Proteins, Pathway, Type Ib Pseudohypoparathyroidisms, OAMB-AS, FZD4S, STRUBBELIG, Monitorings, signal transduction by conformational transition, integral to membrane, G protein coupled receptor, Procedure, Guanine Nucleotide Coupling Protein, signal transduction by trans-phosphorylation, FzE4, Gene Expression, Heterotrimeric, signaling cascade, OAMB-1a, Dmoa1, Diseases, EVR1, Genetic Materials, Parathyroid Hormone-Related Peptide Receptor, simple tissue, internal to cell, Transduction, PTH PTHrP Receptor, Genetic Material, activation, OAMB, Heterotrimeric G Proteins, PTH-PTHrP, DmelCG3856, Transcriptome Profilings, System, signs, oamb, Heterotrimeric GTP-Binding Protein, INSDC_feature:gene, Methodological, Methodological Study, Type Ib Pseudohypoparathyroidism, Treatments, Parathyroid Hormone Receptor, disease, Kidneys, Rare, G Proteins, Parathyroid Hormone Receptor 1, DMDA, Gene Expression Analyses, \"Pseudohypoparathyroidism type I A (disorder)\" EXACT [SNOMEDCT_2005_07_31:58833000], signaling pathway, Specificity and Sensitivity, Patient, Material, PTH-Related Protein Receptor, Cistron, Expression Analysis, Orphan Diseases, AT1G11140, other disease, Signal Transduction Systems, Type Ia Pseudohypoparathyroidism, Mechanobiology, Procedures, Effects, Systems Pharmacology, PFE, Receptor-Mediated, Gene, Pseudohypoparathyroidism Type 1B, Signal Transduction System, Network, protein-containing complex, TYPE, PTH-Related Peptide, CG12298, Gene Expression Profilings, DAGA4, Signal Transduction, mRNA Differential Displays, Gene Expression Pattern Analysis, polypeptide chain, reduced, integral component of membrane, Gene Products, Studies, disease or disorder, Mood, Drug-Target Networks, Osteodystrophy, tiny, MAM, GPCR, Pseudohypoparathyroidism Type 1Bs, SCG3, GTP-Binding Proteins, Technique, Albright Hereditary, Maternally, DmOAMB, DmOctalpha1Rb, protoplasm, Orphan Disease, Drug Target Network, Genetic, protoplast, Parathyroid Hormone, Maternally Inherited, mei-1794, Dynamics Simulations, Albright Hereditary Osteodystrophy with Multiple Hormone Resistance, dysfunction, Signal, Transcriptomics, Signal Pathways, Transcript Expression, Transcriptome Analysis, Molecular Dynamics Simulations, Signal Transduction Pathway, Monitoring, Pthr1, non-neoplastic, Study, signalling pathway, GTP-Regulatory Protein, Maternal Effect, G Protein, PTHLP Receptor, PTH-Related Protein, PTHrP, Clients, PTHR1, Heterotrimeric G-Proteins, G-Proteins, region of membrane, disorder, Sensitivity, signal transduction by cis-phosphorylation, SRF9, OctR, Expression Analyses, CG15698, PTH-Related Peptide Receptor, Signal Pathway, single organism signaling., G-Protein, small, Profiling, Disease, data, Guanine Nucleotide Regulatory Proteins, Transcriptome, findings, DmOCT1B, protein complex, Affects, Proteins, disorders, Receptor-Mediated Signal Transductions, function, medical condition, OctR1, Maternal Effects, Cistrons, FEVR, Client, PHP Ia, LGMD2C, PTHrP Receptor, STRUBBELIG-RECEPTOR FAMILY 9, Maternal, Simulations, Differential Display, Transcript Expression Analyses, native protein, Heterotrimeric GTP Binding Proteins, natural protein, GTP-Regulatory, Receptor-Mediated Signal Transduction, Protein, Systems, chemical analysis, Drug-Target Network, whole membrane, condition, techniques, Pseudohypoparathyroidism, signalling cascade, Fz-4, mRNA Differential Display, OAMB-K3, Rare Disease, Fz4, Dynamic, \"Pseudo-hypoparathyroidism\" EXACT [SNOMEDCT_2005_07_31:267479004], Gene Expression Monitoring, transmembrane, Hereditary Osteodystrophy, PTHLP, DMDA1, Transcriptome Profiling, SNSR6, mRNA, underdeveloped, SNSR4, Dub, Oamb a, Oamb b, Specificity, Inherited Maternally, Dynamics, patient, Differential Displays, pathophysiology, GTP-Binding, \"Albright's hereditary osteodystrophy\" EXACT [CSP2005:1849-7959], Heterotrimeric G, Transcriptome Analyses, GCR2, Protein Gene Products, Type Ia, Type Ib, Orphan, extracellular, Gene Proteins, Heterotrimeric G-Protein, signalling process, Therapeutic, G-PROTEIN COUPLED RECEPTOR 2, Pharmacology, SCARMD2, GTP Regulatory Proteins, Drug-Target, Treatment, Simulation, assay, Receptor, MRGX1, T19D16.8, SCM, Parathyroid Hormone Like Peptide Receptor, MRGX4, methodology"],"name_synonyms":["G-Protein, F14G24.19, GTP Regulatory Protein, Guanine Nucleotide Regulatory Proteins, GTP Binding Proteins, DmOCT1B, cycline, GTP Binding Protein, OAMB-AS, FZD4S, GTP-Regulatory Proteins, CG3938., DmcyclinE, fond, Proteins, F14G24_19, G protein coupled receptor, cycE, OctR1, CycEI, Cyc E, br37, FEVR, Guanine Nucleotide Coupling Protein, l(2)br37, CYCLE, cdi7, FzE4, OAMB-1a, Dmoa1, l(2)k02514, Ccne, DmCycE, cyclinE, BG:DS07108.3, GTP-Regulatory, Protein, EVR1, Cdi7, CDI7, GTP-Binding Protein, CyeE, GPCR, l(2)05206, Fz-4, OAMB-K3, CD344, DmOAMB, DmOctalpha1Rb, Fz4, OAMB, CYCE, l(2)k02602, DmelCG3856, VTS20631, SNSR6, Dm-OAMB, SNSR4, DmelCG3938, CyclE, Oamb a, Oamb b, l(2)35Dd, GALR4, 3938, oamb, GTP-Binding, DmcycE, GCR2, l(2)k05007, D-CycE, dm-cycE, G Proteins, GTP-Regulatory Protein, G Protein, l35Dd, hFz4, G-PROTEIN COUPLED RECEPTOR 2, GALRL, G-Proteins, GTP Regulatory Proteins, OctR, MRGX1, CG15698, PGR7, MRGX4, CG3856"],"pubmed_title_synonyms":["AT1G11140, F14G24.19, Disease, DmOCT1B, OAMB-AS, FZD4S, STRUBBELIG, F14G24_19, G protein coupled receptor, function, OctR1, FEVR, CG12298, STRUBBELIG-RECEPTOR FAMILY 9, SUB, Mutations, FzE4, OAMB-1a, Dmoa1, DmelCG12298, EVR1, SCRAMBLED, GPCR, Fz-4, KIF20A, OAMB-K3, CD344, DmOAMB, Rare Disease, DmOctalpha1Rb, Orphan Disease, Fz4, OAMB, DmelCG3856, VTS20631, SNSR6, Dm-OAMB, SNSR4, mei-1794, Dub, Oamb a, Oamb b, GALR4, oamb, GCR2, Orphan, Rare, hFz4, signalling process, G-PROTEIN COUPLED RECEPTOR 2, GALRL, SRF9, OctR, MRGX1, CG15698, PGR7, T19D16.8, Orphan Diseases, SCM, MRGX4, single organism signaling., CG3856"],"description_synonyms":["G-Protein, GTP Regulatory Protein, G Proteins, DmelCG17820, Guanine Nucleotide Regulatory Proteins, GTP Binding Proteins, GTP-Regulatory Protein, G Protein, GTP Binding Protein, GTP-Regulatory, data., GTP-Regulatory Proteins, Protein, Proteins, G-Proteins, GTP Regulatory Proteins, GTP-Binding Protein, GTP-Binding, CG17820, activation, Guanine Nucleotide Coupling Protein"],"additional_accession":[]},"is_claimable":false,"name":"GPCR Cubic Ternary Complex with G protein Cycle, Redfern-Nichols 2023","description":"A model of G protein activation using ordinary differential equations. Used to fit to experimental data obtained from the TRUPATH platform.","dates":{"last_modification":"2025-05-22","publication":"2025-05-22","submission":"2023-06-22"},"accession":"MODEL2306220001","cross_references":{"pubmed":["40392940"],"biomodels__db":["MODEL2306220001"]}}