4Y5X

Diabody 305 complex with EpoR

4Y5X の概要

• エントリーDOI: 10.2210/pdb4y5x/pdb
• 関連するPDBエントリー: 4Y5V 4Y5Y
• 分子名称: diabody 310 VL domain, diabody 310 VH domain, Erythropoietin receptor, ... (6 entities in total)
• 機能のキーワード: diabody complex, receptor, protein binding-immune system complex, protein binding/immune system
• 由来する生物種: Homo sapiens; 詳細
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein. Isoform EPOR-S: Secreted : P19235
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 207053.28

構造登録者

Moraga, I.,Guo, F.,Ozkan, E.,Jude, K.M.,Garcia, K.C. (登録日: 2015-02-12, 公開日: 2015-03-18, 最終更新日: 2024-11-06)

主引用文献

Moraga, I.,Wernig, G.,Wilmes, S.,Gryshkova, V.,Richter, C.P.,Hong, W.J.,Sinha, R.,Guo, F.,Fabionar, H.,Wehrman, T.S.,Krutzik, P.,Demharter, S.,Plo, I.,Weissman, I.L.,Minary, P.,Majeti, R.,Constantinescu, S.N.,Piehler, J.,Garcia, K.C.
Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands.
Cell, 160:1196-1208, 2015

PubMed 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.

PubMed: 25728669
DOI: 10.1016/j.cell.2015.02.011

実験手法

X-RAY DIFFRACTION (3.15 Å)