6E3L

Interferon gamma signalling complex with IFNGR1 and IFNGR2

Summary for 6E3L

• Entry DOI: 10.2210/pdb6e3l/pdb
• Related: 6E3K
• Descriptor: Interferon gamma, Interferon gamma receptor 1, Interferon gamma receptor 2, ... (8 entities in total)
• Functional Keywords: cytokine receptor, protein complex, protein engineering, cytokine
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 147235.68

Authors

Jude, K.M.,Mendoza, J.L.,Garcia, K.C. (deposition date: 2018-07-14, release date: 2019-02-27, Last modification date: 2024-10-23)

Primary citation

Mendoza, J.L.,Escalante, N.K.,Jude, K.M.,Sotolongo Bellon, J.,Su, L.,Horton, T.M.,Tsutsumi, N.,Berardinelli, S.J.,Haltiwanger, R.S.,Piehler, J.,Engleman, E.G.,Garcia, K.C.
Structure of the IFN gamma receptor complex guides design of biased agonists.
Nature, 567:56-60, 2019

PubMed Abstract: 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.

PubMed: 30814731
DOI: 10.1038/s41586-019-0988-7

Experimental method

X-RAY DIFFRACTION (3.8 Å)