PDBsum entry 3qb7

Cytokine/cytokine receptor

PDB id: 3qb7

Contents

Protein chains

123 a.a.

191 a.a.

183 a.a.

Ligands

NAG-NAG ×2

SO4 ×2

NAG ×2

PDB id:

3qb7

Name:

Cytokine/cytokine receptor

Title:

Interleukin-4 mutant rga bound to cytokine receptor common gamma

Structure:

Interleukin 4. Chain: a, b. Fragment: unp residues 25-153. Engineered: yes. Mutation: yes. Cytokine receptor common subunit gamma. Chain: c, d. Fragment: unp residues 55-254. Synonym: interleukin-2 receptor subunit gamma, il-2 receptor subunit

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: il4. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Gene: il2rg. Expression_system_taxid: 7111

Resolution:

3.25Å R-factor: 0.234 R-free: 0.292

Authors:

D.L.Bates,I.S.Junttila,R.J.Creusot,I.Moraga,P.Lupardus,C.G.Fathman, W.E.Paul,K.C.Garcia

Key ref:

I.S.Junttila et al. (2012). Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines. Nat Chem Biol, 8, 990-998. PubMed id: 23103943

Date:

12-Jan-11 Release date: 25-Apr-12

Protein chains

P05112  (IL4_HUMAN) -  Interleukin-4 from Homo sapiens

Seq: 153 a.a.

Struc: 123 a.a.*

Protein chain

P31785  (IL2RG_HUMAN) -  Cytokine receptor common subunit gamma from Homo sapiens

Seq: 369 a.a.

Struc: 191 a.a.*

Protein chain

P31785  (IL2RG_HUMAN) -  Cytokine receptor common subunit gamma from Homo sapiens

Seq: 369 a.a.

Struc: 183 a.a.*

* PDB and UniProt seqs differ at 8 residue positions (black crosses)

Nat Chem Biol 8:990-998 (2012)

PubMed id: 23103943

Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines.

I.S.Junttila, R.J.Creusot, I.Moraga, D.L.Bates, M.T.Wong, M.N.Alonso, M.M.Suhoski, P.Lupardus, M.Meier-Schellersheim, E.G.Engleman, P.J.Utz, C.G.Fathman, W.E.Paul, K.C.Garcia.

ABSTRACT

Cytokines dimerize their receptors, with the binding of the 'second chain' triggering signaling. In the interleukin (IL)-4 and IL-13 system, different cell types express varying numbers of alternative second receptor chains (γc or IL-13Rα1), forming functionally distinct type I or type II complexes. We manipulated the affinity and specificity of second chain recruitment by human IL-4. A type I receptor-selective IL-4 'superkine' with 3,700-fold higher affinity for γc was three- to ten-fold more potent than wild-type IL-4. Conversely, a variant with high affinity for IL-13Rα1 more potently activated cells expressing the type II receptor and induced differentiation of dendritic cells from monocytes, implicating the type II receptor in this process. Superkines showed signaling advantages on cells with lower second chain numbers. Comparative transcriptional analysis reveals that the superkines induce largely redundant gene expression profiles. Variable second chain numbers can be exploited to redirect cytokines toward distinct cell subsets and elicit new actions, potentially improving the selectivity of cytokine therapy.