Probing the binding of interleukin-23 to individual receptor components and the IL-23 heteromeric receptor complex in living cells using NanoBRET.
IL12Rβ1
IL12p40
IL23R
IL23p19
NanoBRET
cytokine receptor
interleukin-23
ligand binding
receptor oligomerization
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
20 01 2022
20 01 2022
Historique:
received:
05
01
2021
revised:
06
04
2021
accepted:
04
05
2021
pubmed:
27
5
2021
medline:
3
3
2022
entrez:
26
5
2021
Statut:
ppublish
Résumé
Interleukin-23 (IL-23) is a pro-inflammatory cytokine involved in the host defense against pathogens but is also implicated in the development of several autoimmune disorders. The IL-23 receptor has become a key target for drug discovery, but the exact mechanism of the receptor ligand interaction remains poorly understood. In this study the affinities of IL-23 for its individual receptor components (IL23R and IL12Rβ1) and the heteromeric complex formed between them have been measured in living cells using NanoLuciferase-tagged full-length proteins. Here, we demonstrate that TAMRA-tagged IL-23 has a greater than 7-fold higher affinity for IL12Rβ1 than IL23R. However, in the presence of both receptor subunits, IL-23 affinity is increased more than three orders of magnitude to 27 pM. Furthermore, we show that IL-23 induces a potent change in the position of the N-terminal domains of the two receptor subunits, consistent with a conformational change in the heteromeric receptor structure.
Identifiants
pubmed: 34038748
pii: S2451-9456(21)00219-1
doi: 10.1016/j.chembiol.2021.05.002
pmc: PMC8790524
pii:
doi:
Substances chimiques
IL23R protein, human
0
Interleukin-23
0
Receptors, Interleukin
0
Luciferases
EC 1.13.12.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
19-29.e6Subventions
Organisme : Medical Research Council
ID : MR/N020081/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S507027/1
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests P.D.C, A.B., and Z.S. are employees of and shareholders in GSK.
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