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Structure of the IFNγ receptor complex guides design of biased agonists.

التفاصيل البيبلوغرافية
العنوان: Structure of the IFNγ receptor complex guides design of biased agonists.
المؤلفون: Mendoza JL; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.; Institute for Molecular Engineering and Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA., Escalante NK; Stanford Blood Center, Palo Alto, CA, USA.; Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA., Jude KM; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA., Sotolongo Bellon J; Division of Biophysics, Department of Biology, University of Osnabruck, Osnabruck, Germany., Su L; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA., Horton TM; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA., Tsutsumi N; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA., Berardinelli SJ; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA., Haltiwanger RS; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA., Piehler J; Division of Biophysics, Department of Biology, University of Osnabruck, Osnabruck, Germany., Engleman EG; Stanford Blood Center, Palo Alto, CA, USA.; Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA., Garcia KC; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.
المصدر: Nature [Nature] 2019 Mar; Vol. 567 (7746), pp. 56-60. Date of Electronic Publication: 2019 Feb 27.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature
أسماء مطبوعة: Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
مواضيع طبية MeSH: Drug Design*, Interferon-gamma/*agonists , Interferon-gamma/*immunology , Receptors, Interferon/*chemistry , Receptors, Interferon/*metabolism, B7-H1 Antigen/biosynthesis ; B7-H1 Antigen/genetics ; Cell Line, Tumor ; Drug Partial Agonism ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Histocompatibility Antigens Class I/biosynthesis ; Histocompatibility Antigens Class I/genetics ; Humans ; Interferon-gamma/chemistry ; Interferon-gamma/genetics ; Ligands ; Models, Molecular ; Mutation ; Mycobacterium Infections/genetics ; Mycobacterium Infections/immunology ; Protein Stability ; Receptors, Interferon/genetics ; Signal Transduction ; Structure-Activity Relationship ; Interferon gamma Receptor
مستخلص: The cytokine interferon-γ (IFNγ) is a central coordinator of innate and adaptive immunity, but its highly pleiotropic actions have diminished its prospects for use as an immunotherapeutic agent. Here, we took a structure-based approach to decoupling IFNγ pleiotropy. We engineered an affinity-enhanced variant of the ligand-binding chain of the IFNγ receptor IFNγR1, which enabled us to determine the crystal structure of the complete hexameric (2:2:2) IFNγ-IFNγR1-IFNγR2 signalling complex at 3.25 Å resolution. The structure reveals the mechanism underlying deficits in IFNγ responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFNγR2, which impairs assembly of the full signalling complex. The topology of the hexameric complex offers a blueprint for engineering IFNγ variants to tune IFNγ receptor signalling output. Unexpectedly, we found that several partial IFNγ agonists exhibited biased gene-expression profiles. These biased agonists retained the ability to induce upregulation of major histocompatibility complex class I antigen expression, but exhibited impaired induction of programmed death-ligand 1 expression in a wide range of human cancer cell lines, offering a route to decoupling immunostimulatory and immunosuppressive functions of IFNγ for therapeutic applications.
التعليقات: Comment in: Immunol Cell Biol. 2019 May;97(5):442-444. (PMID: 31131497)
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معلومات مُعتمدة: K01 CA175127 United States CA NCI NIH HHS; HD090156 United States NH NIH HHS; 5R01CA177684 United States NH NIH HHS; 1U19AI109662 United States NH NIH HHS; R37 AI051321 United States AI NIAID NIH HHS; U19 AI109662 United States AI NIAID NIH HHS; R01 HD090156 United States HD NICHD NIH HHS; U54 CA209971 United States CA NCI NIH HHS; R01 AI051321 United States AI NIAID NIH HHS; R01-AI51321 United States NH NIH HHS; United States HHMI Howard Hughes Medical Institute; R01 CA177684 United States CA NCI NIH HHS; P41 GM103393 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (B7-H1 Antigen)
0 (CD274 protein, human)
0 (Histocompatibility Antigens Class I)
0 (Ligands)
0 (Receptors, Interferon)
82115-62-6 (Interferon-gamma)
تواريخ الأحداث: Date Created: 20190301 Date Completed: 20190730 Latest Revision: 20231213
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6561087
DOI: 10.1038/s41586-019-0988-7
PMID: 30814731
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-4687
DOI:10.1038/s41586-019-0988-7