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.