Poster Presentation 2014 International Biophysics Congress

How protein ligands affect the conformation of the erythropoietin receptor dimer (#379)

Michael Corbett 1 , David Poger 1 , Alan E Mark 1
  1. SCMB, University of Queensland, Brisbane, QLD, Australia
The erythropoietin receptor (EpoR) and other type-I cytokine receptors such as the growth hormone receptor and the prolactin receptor are major membrane receptors involved in signal transduction. EpoR is an important therapeutical target for the treatment of anaemia in patients with renal failure or undergoing chemotherapy. As these receptors are active as dimers, understanding the mechanism induced by ligand binding and leading to activation is crucial. Using unbiased atomistic simulation techniques, we compared how different ligands (erythropoietin and agonist and antagonist erythropoietin mimetic peptides) bound to the extracellular domain of the EpoR dimer affected the relative orientations of the two chains. The starting configurations were derived from crystal structures of the extracellular domain of the EpoR dimer bound to erythropoietin or to a mimetic peptide. In all the simulations of the ligand-bound EpoR dimers, the EpoR chains relaxed to a T-like relative arrangement. In contrast, when erythropoietin was removed from the dimer, the chains underwent a clockwise rotation of up to 90° while coming closer to each other. The comparison of the motions in the simulations of the EpoR dimer bound to an agonist and antagonist liagnd did not show a consistent trend in the relative conformational change between the EpoR chains leading to activation. Interestingly, the simulations of the erythropoietin-bound dimer sampled configurations closely related to the crystal structures of the EpoR dimer associated with agonist and antagonist erythropoietin mimetic peptides. This suggests that the mechanism of activation of the EpoR cannot be inferred from the relative arrangement of the extracellular domain observed in the different crystal structures of EpoR in a bound state. Overall, the simulations indicate that the transmembrane regions may be necessary to model accurately the structural changes within the EpoR dimer involved in activation.