PDBsum entry 4y5v

Protein binding/immune system

PDB id: 4y5v

Contents

Protein chains

121 a.a.

111 a.a.

206 a.a.

206 a.a.

191 a.a.

Ligands

GOL ×15

PGE

PEG

Waters ×301

References listed in PDB file

Key reference

• Title: Tuning cytokine receptor signaling by re-Orienting dimer geometry with surrogate ligands.
• Authors: 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.
• Ref.: Cell, 2015, 160, 1196-1208. [DOI no: 10.1016/j.cell.2015.02.011]
• PubMed id: 25728669

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.