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Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1

(2018) IMMUNITY. 48(1). p.45-58
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Abstract
Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rb1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23: antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.
Keywords
INTERLEUKIN 23 RECEPTOR, ANTI-INTERLEUKIN-23 MONOCLONAL-ANTIBODY, BOWEL-DISEASE, HETERODIMERIC CYTOKINE, SEVERE PSORIASIS, MAMMALIAN-CELLS, PHASE-III, T-CELLS, COMPLEX, PROTEIN

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Chicago
Bloch, Yehudi, Laura Bouchareychas, Romain Merceron, Katarzyna Skladanowska, Lien Van den Bossche, Sammy Detry, Srinath Govindarajan, et al. 2018. “Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1.” Immunity 48 (1): 45–58.
APA
Bloch, Y., Bouchareychas, L., Merceron, R., Skladanowska, K., Van den Bossche, L., Detry, S., Govindarajan, S., et al. (2018). Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1. IMMUNITY, 48(1), 45–58.
Vancouver
1.
Bloch Y, Bouchareychas L, Merceron R, Skladanowska K, Van den Bossche L, Detry S, et al. Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1. IMMUNITY. 2018;48(1):45–58.
MLA
Bloch, Yehudi, Laura Bouchareychas, Romain Merceron, et al. “Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1.” IMMUNITY 48.1 (2018): 45–58. Print.
@article{8544644,
  abstract     = {Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rb1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23: antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.},
  author       = {Bloch, Yehudi and Bouchareychas, Laura and Merceron, Romain and Skladanowska, Katarzyna and Van den Bossche, Lien and Detry, Sammy and Govindarajan, Srinath and Elewaut, Dirk and Haerynck, Filomeen and Dullaers, Melissa and Adamopoulos, Iannis E and Savvides, Savvas},
  issn         = {1074-7613},
  journal      = {IMMUNITY},
  language     = {eng},
  number       = {1},
  pages        = {45--58},
  title        = {Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12R\ensuremath{\beta}1},
  url          = {http://dx.doi.org/10.1016/j.immuni.2017.12.008},
  volume       = {48},
  year         = {2018},
}

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