PDBsum entry 4y5x

Protein binding/immune system

PDB id: 4y5x

Contents

Protein chains

124 a.a.

111 a.a.

205 a.a.

Ligands

PEG ×17

FLC

Waters ×28

PDB id:

4y5x

Name:

Protein binding/immune system

Title:

Diabody 305 complex with epor

Structure:

Diabody 310 vl domain. Chain: a, d, g, j. Engineered: yes. Diabody 310 vh domain. Chain: b, e, h, k. Engineered: yes. Erythropoietin receptor. Chain: c, f, i, l. Synonym: epo-r.

Source:

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

Resolution:

3.15Å R-factor: 0.204 R-free: 0.241

Authors:

I.Moraga,F.Guo,E.Ozkan,K.M.Jude,K.C.Garcia

Key ref:

I.Moraga et al. (2015). Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands. Cell, 160, 1196-1208. PubMed id: 25728669 DOI: 10.1016/j.cell.2015.02.011

Date:

12-Feb-15 Release date: 18-Mar-15

Protein chains

No UniProt id for this chain

Struc: 124 a.a.

Protein chains

Q5NV67  (Q5NV67_HUMAN) -  V1-11 protein (Fragment) from Homo sapiens

Seq: 99 a.a.

Struc: 111 a.a.*

Protein chains

P19235  (EPOR_HUMAN) -  Erythropoietin receptor from Homo sapiens

Seq: 508 a.a.

Struc: 205 a.a.*

* PDB and UniProt seqs differ at 9 residue positions (black crosses)

DOI no: 10.1016/j.cell.2015.02.011

Cell 160:1196-1208 (2015)

PubMed id: 25728669

Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands.

I.Moraga, G.Wernig, S.Wilmes, V.Gryshkova, C.P.Richter, W.J.Hong, R.Sinha, F.Guo, H.Fabionar, T.S.Wehrman, P.Krutzik, S.Demharter, I.Plo, I.L.Weissman, P.Minary, R.Majeti, S.N.Constantinescu, J.Piehler, K.C.Garcia.

ABSTRACT

Most cell-surface receptors for cytokines and growth factors signal as dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to "tune" signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin (EPO) and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism, and structures of these DA/EpoR complexes differed in EpoR dimer orientation and proximity. Diabodies also elicited biased or differential activation of signaling pathways and gene expression profiles compared to EPO. Non-signaling diabodies inhibited proliferation of erythroid precursors from patients with a myeloproliferative neoplasm due to a constitutively active JAK2V617F mutation. Thus, intracellular oncogenic mutations causing ligand-independent receptor activation can be counteracted by extracellular ligands that re-orient receptors into inactive dimer topologies. This approach has broad applications for tuning signaling output for many dimeric receptor systems.