Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells .It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade . The half-maximal response in a cellular proliferation assay is evoked at an erythropoietin concentration of 10 pM , 10-2 of its Kd value for erythropoietin-EPOR binding site 1 (Kd [almost equal to] 1 nM), and 10-5 of the Kd for erythropoietin-EPOR binding site 2 (Kd [almost equal to] 1 micro M) . Overall half-maximal binding (IC50) of cell-surface receptors is produced with [tilde operator] 0.18 nM erythropoietin, indicating that only [tilde operator] 6% of the receptors would be bound in the presence of 10 pM erythropoietin. Other effective erythropoietin-mimetic ligands that dimerize receptors can evoke the same cellular responses [5,6] but much less efficiently, requiring concentrations close to their Kd values ([tilde operator] 0.1 micro M). The crystal structure of erythropoietin complexed to the extracellular ligand-binding domains of the erythropoietin receptor, determined at 1.9 Angstrom from two crystal forms, shows that erythropoietin imposes a unique 120 degrees angular relationship and orientation that is responsible for optimal signalling through intracellular kinase pathways.