6MOG

Dimeric DARPin C_R3

Summary for 6MOG

• Entry DOI: 10.2210/pdb6mog/pdb
• Descriptor: DARPin C_R3, 1,2-ETHANEDIOL, TRIETHYLENE GLYCOL, ... (4 entities in total)
• Functional Keywords: darpin, biosynthetic protein
• Biological source: synthetic construct
• Total number of polymer chains: 2
• Total formula weight: 35901.07

Authors

Jude, K.M.,Mohan, K.,Garcia, K.C. (deposition date: 2018-10-04, release date: 2019-06-05, Last modification date: 2024-04-03)

Primary citation

Mohan, K.,Ueda, G.,Kim, A.R.,Jude, K.M.,Fallas, J.A.,Guo, Y.,Hafer, M.,Miao, Y.,Saxton, R.A.,Piehler, J.,Sankaran, V.G.,Baker, D.,Garcia, K.C.
Topological control of cytokine receptor signaling induces differential effects in hematopoiesis.
Science, 364:-, 2019

PubMed Abstract: Although tunable signaling by G protein-coupled receptors can be exploited through medicinal chemistry, a comparable pharmacological approach has been lacking for the modulation of signaling through dimeric receptors, such as those for cytokines. We present a strategy to modulate cytokine receptor signaling output by use of a series of designed C2-symmetric cytokine mimetics, based on the designed ankyrin repeat protein (DARPin) scaffold, that can systematically control erythropoietin receptor (EpoR) dimerization orientation and distance between monomers. We sampled a range of EpoR geometries by varying intermonomer angle and distance, corroborated by several ligand-EpoR complex crystal structures. Across the range, we observed full, partial, and biased agonism as well as stage-selective effects on hematopoiesis. This surrogate ligand strategy opens access to pharmacological modulation of therapeutically important cytokine and growth factor receptor systems.

PubMed: 31123111
DOI: 10.1126/science.aav7532

Experimental method

X-RAY DIFFRACTION (1.21 Å)