5NJD

Structure of Interleukin 23 in complex with Briakinumab FAb

Summary for 5NJD

• Entry DOI: 10.2210/pdb5njd/pdb
• Descriptor: Interleukin-12 subunit beta, Interleukin-23 subunit alpha, Briakinumab FAb Light chain, ... (6 entities in total)
• Functional Keywords: antagonist, antibody, extracellular region, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 24
• Total formula weight: 701055.70

Authors

Bloch, Y.,Savvides, S.N. (deposition date: 2017-03-28, release date: 2018-01-03, Last modification date: 2024-10-16)

Primary citation

Bloch, Y.,Bouchareychas, L.,Merceron, R.,Skladanowska, K.,Van den Bossche, L.,Detry, S.,Govindarajan, S.,Elewaut, D.,Haerynck, F.,Dullaers, M.,Adamopoulos, I.E.,Savvides, S.N.
Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12R beta 1.
Immunity, 48:45-58.e6, 2018

PubMed 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-12Rβ1 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.

PubMed: 29287995
DOI: 10.1016/j.immuni.2017.12.008

Experimental method

X-RAY DIFFRACTION (3.9 Å)