| Structural highlights
6e3k is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| Related: | 6e3l |
| Gene: | IFNG (HUMAN), IFNGR1 (HUMAN), IFNGR2, IFNGT1 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[IFNG_HUMAN] In Caucasians, genetic variation in IFNG is associated with the risk of aplastic anemia (AA) [MIM:609135]. AA is a rare disease in which the reduction of the circulating blood cells results from damage to the stem cell pool in bone marrow. In most patients, the stem cell lesion is caused by an autoimmune attack. T-lymphocytes, activated by an endogenous or exogenous, and most often unknown antigenic stimulus, secrete cytokines, including IFN-gamma, which would in turn be able to suppress hematopoiesis. [INGR2_HUMAN] Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency;Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency;Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency. The disease is caused by mutations affecting the gene represented in this entry. [INGR1_HUMAN] Defects in IFNGR1 are a cause of Mendelian susceptibility to mycobacterial disease (MSMD) [MIM:209950]; also known as familial disseminated atypical mycobacterial infection. This rare condition confers predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine and environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. The pathogenic mechanism underlying MSMD is the impairment of interferon-gamma mediated immunity whose severity determines the clinical outcome. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance.[1] [2]
Function
[IFNG_HUMAN] Produced by lymphocytes activated by specific antigens or mitogens. IFN-gamma, in addition to having antiviral activity, has important immunoregulatory functions. It is a potent activator of macrophages, it has antiproliferative effects on transformed cells and it can potentiate the antiviral and antitumor effects of the type I interferons. [INGR2_HUMAN] Associates with IFNGR1 to form a receptor for the cytokine interferon gamma (IFNG) (PubMed:8124716, PubMed:7673114,PubMed:7615558). Ligand binding stimulates activation of the JAK/STAT signaling pathway (PubMed:8124716, PubMed:7673114, PubMed:15356148). Required for signal transduction in contrast to other receptor subunit responsible for ligand binding (PubMed:7673114).[3] [4] [5] [6] [INGR1_HUMAN] Receptor for interferon gamma. Two receptors bind one interferon gamma dimer.
Publication Abstract from PubMed
The cytokine interferon-gamma (IFNgamma) 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 IFNgamma pleiotropy. We engineered an affinity-enhanced variant of the ligand-binding chain of the IFNgamma receptor IFNgammaR1, which enabled us to determine the crystal structure of the complete hexameric (2:2:2) IFNgamma-IFNgammaR1-IFNgammaR2 signalling complex at 3.25 A resolution. The structure reveals the mechanism underlying deficits in IFNgamma responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFNgammaR2, which impairs assembly of the full signalling complex. The topology of the hexameric complex offers a blueprint for engineering IFNgamma variants to tune IFNgamma receptor signalling output. Unexpectedly, we found that several partial IFNgamma 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 IFNgamma for therapeutic applications.
Structure of the IFNgamma receptor complex guides design of biased agonists.,Mendoza JL, Escalante NK, Jude KM, Sotolongo Bellon J, Su L, Horton TM, Tsutsumi N, Berardinelli SJ, Haltiwanger RS, Piehler J, Engleman EG, Garcia KC Nature. 2019 Mar;567(7746):56-60. doi: 10.1038/s41586-019-0988-7. Epub 2019 Feb, 27. PMID:30814731[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jouanguy E, Lamhamedi-Cherradi S, Altare F, Fondaneche MC, Tuerlinckx D, Blanche S, Emile JF, Gaillard JL, Schreiber R, Levin M, Fischer A, Hivroz C, Casanova JL. Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J Clin Invest. 1997 Dec 1;100(11):2658-64. PMID:9389728 doi:10.1172/JCI119810
- ↑ Jouanguy E, Dupuis S, Pallier A, Doffinger R, Fondaneche MC, Fieschi C, Lamhamedi-Cherradi S, Altare F, Emile JF, Lutz P, Bordigoni P, Cokugras H, Akcakaya N, Landman-Parker J, Donnadieu J, Camcioglu Y, Casanova JL. In a novel form of IFN-gamma receptor 1 deficiency, cell surface receptors fail to bind IFN-gamma. J Clin Invest. 2000 May;105(10):1429-36. PMID:10811850 doi:10.1172/JCI9166
- ↑ Rosenzweig SD, Schwartz OM, Brown MR, Leto TL, Holland SM. Characterization of a dipeptide motif regulating IFN-gamma receptor 2 plasma membrane accumulation and IFN-gamma responsiveness. J Immunol. 2004 Sep 15;173(6):3991-9. PMID:15356148
- ↑ Sakatsume M, Igarashi K, Winestock KD, Garotta G, Larner AC, Finbloom DS. The Jak kinases differentially associate with the alpha and beta (accessory factor) chains of the interferon gamma receptor to form a functional receptor unit capable of activating STAT transcription factors. J Biol Chem. 1995 Jul 21;270(29):17528-34. PMID:7615558
- ↑ Kotenko SV, Izotova LS, Pollack BP, Mariano TM, Donnelly RJ, Muthukumaran G, Cook JR, Garotta G, Silvennoinen O, Ihle JN, et al.. Interaction between the components of the interferon gamma receptor complex. J Biol Chem. 1995 Sep 8;270(36):20915-21. PMID:7673114
- ↑ Soh J, Donnelly RJ, Kotenko S, Mariano TM, Cook JR, Wang N, Emanuel S, Schwartz B, Miki T, Pestka S. Identification and sequence of an accessory factor required for activation of the human interferon gamma receptor. Cell. 1994 Mar 11;76(5):793-802. PMID:8124716
- ↑ Mendoza JL, Escalante NK, Jude KM, Sotolongo Bellon J, Su L, Horton TM, Tsutsumi N, Berardinelli SJ, Haltiwanger RS, Piehler J, Engleman EG, Garcia KC. Structure of the IFNgamma receptor complex guides design of biased agonists. Nature. 2019 Mar;567(7746):56-60. doi: 10.1038/s41586-019-0988-7. Epub 2019 Feb, 27. PMID:30814731 doi:http://dx.doi.org/10.1038/s41586-019-0988-7
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