PDBsum entry 3duh

Immune system/cytokine

PDB id

3duh

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Contents

			Protein chains

					300 a.a. *


					137 a.a. *


					137 a.a. *

			Ligands

					NAG ×2

			Waters ×200

* Residue conservation analysis

PDB id:

3duh

Links

Name:

Immune system/cytokine

Title:

Structure of interleukin-23

Structure:

Interleukin-12 subunit beta. Chain: a, b. Synonym: il-12b, il-12 subunit p40, cytotoxic lymphocyte maturation factor 40 kda subunit, clmf p40, nk cell stimulatory factor chain 2, nksf2. Engineered: yes. Interleukin-23 subunit alpha. Chain: c, d. Synonym: il-23 subunit alpha, interleukin-23 subunit p19, il-23p19.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: il12b, nksf2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: il23a, sgrf, unq2498/pro5798.

Resolution:

2.30Å

R-factor:

0.230

R-free:

0.268

Authors:

P.J.Lupardus,K.C.Garcia

Key ref:

P.J.Lupardus and K.C.Garcia (2008). The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12. J Mol Biol, 382, 931-941. PubMed id: 18680750 DOI: 10.1016/j.jmb.2008.07.051

Date:

17-Jul-08

Release date:

19-Aug-08

PROCHECK

	Headers

	References

Protein chains

P29460 (IL12B_HUMAN) - Interleukin-12 subunit beta from Homo sapiens

Seq: Struc:					328 a.a. 300 a.a.*

Protein chain

Q9NPF7 (IL23A_HUMAN) - Interleukin-23 subunit alpha from Homo sapiens

Seq: Struc:					189 a.a. 137 a.a.*

Protein chain

Q9NPF7 (IL23A_HUMAN) - Interleukin-23 subunit alpha from Homo sapiens

Seq: Struc:					189 a.a. 137 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DOI no: 10.1016/j.jmb.2008.07.051	J Mol Biol 382:931-941 (2008)
PubMed id: 18680750

The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12.
P.J.Lupardus, K.C.Garcia.

ABSTRACT

Interleukin (IL)-23 is a recently identified member of the IL-12 family of heterodimeric cytokines that modulate subpopulations of T helper cells, and both IL-12 and IL-23 are attractive targets for therapy of autoimmune diseases. IL-23 is a binary complex of a four-helix bundle cytokine (p19) and a soluble class I cytokine receptor p40. IL-12 and IL-23 share p40 as an alpha-receptor subunit, yet show only 15% sequence homology between their four-helix cytokines p19 and p35, respectively, and signal through different combinations of shared receptors. In order to elucidate the structural basis of p40 sharing, we have determined a 2.3-A crystal structure of IL-23 for comparison to the previously determined structure of IL-12. The docking mode of p19 to p40 is altered compared to p35, deviating by a 'tilt' and 'roll' that results in an altered footprint of p40 on the A and D helices of the respective cytokines. Binding of p19 to p40 is mediated primarily by an arginine residue on helix D of p19 that forms an extensive charge and hydrogen-bonding network with residues at the base of a pocket on p40. This 'arginine pocket' is lined with an inner shell of hydrophobic interactions that are ringed by an outer shell of polar interactions. Comparative analysis indicates that the IL-23 and IL-12 complexes 'mimic' the network of interactions constituting the central arginine pocket despite p19 and p35 having limited sequence homology. The majority of the structural epitopes in the two complexes are composed of unique p19 and p35 pairwise contacts with common residues on p40. Thus, while the critical hotspot is maintained in the two complexes, the majority of the interfaces are structurally distinct and, therefore, provide a basis for the therapeutic targeting of IL-12 versus IL-23 heterodimer formation despite their use of a common receptor subunit.

Selected figure(s)



	Figure 2. Fig. 2. Structure of IL-23. (a) Side view of the IL-23 crystal structure. p19 helices A to D are colored magenta, and p40 domains 1 to 3 are colored blue. The single N-acetylglucosamine residue attached to Asn200 on p40 is shown in red. Disulfide linkages are colored yellow. (b) Face-on view of IL-23. Receptor interaction sites 2 and 3 are highlighted in ovals, and the key site 3-interacting side chain of Trp137 is displayed.		Figure 5. Fig. 5. Comparison of shared and distinct contact surfaces in the IL-23 and IL-12 complexes. (a) Histogram of buried surface area contributed by each p40 residue involved in p19 and/or p35 interaction. (b) Surface representation of p40 (middle panel), with residues interacting with p19 (pink), p35 (green), or p19 and p35 (yellow) highlighted. The p40-interacting surfaces of p19 (left panel in pink) and p35 (right panel in green) are shown with a transparent p40 overlay to demonstrate orientation.

Figures were selected by an automated process.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20974977

F.Rousseau, L.Basset, J.Froger, N.Dinguirard, S.Chevalier, and H.Gascan (2010).
IL-27 structural analysis demonstrates similarities with ciliary neurotrophic factor (CNTF) and leads to the identification of antagonistic variants.

Proc Natl Acad Sci U S A, 107, 19420-19425.

20223216

P.J.Lupardus, M.E.Birnbaum, and K.C.Garcia (2010).
Molecular basis for shared cytokine recognition revealed in the structure of an unusually high affinity complex between IL-13 and IL-13Ralpha2.

Structure, 18, 332-342.

PDB code:

3lb6

19453248

J.Van Limbergen, D.C.Wilson, and J.Satsangi (2009).
The genetics of Crohn's disease.

Annu Rev Genomics Hum Genet, 10, 89.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.