A high-res protein structure yields a blueprint for precision drug design
Researchers led by Ludwig Stanford’sChristopher Garcia reported in an August publication in Cell the 3.4 Å resolution cryoelectron microscopy structure of the extracellular signaling complex of thrombopoietin (Tpo) with its receptor (TpoR)—an interaction essential to hematopoiesis, or the generation of the cellular components of blood. Tpo activation of TpoR is essential to hematopoietic stem cell maintenance as well as platelet production. Loss-of-function mutations in either cause thrombocytopenia—a dangerous deficiency of platelets—and bone marrow failure. Unrestrained TpoR signaling, on the other hand, drives slow-growing cancers known as myeloproliferative neoplasms. The structure deduced by Chris and his colleagues explains how dimerization of TpoR activates its signaling and why certain mutations cause thrombocytopenia. While Tpo agonists that boost platelet production already exist, they bring with them a risk of excessive blood stem cell proliferation, bone marrow fibrosis and an increased incidence of thrombosis. Notably, Chris and his colleagues used their protein structure to design Tpo analogs ranging from antagonists to agonists of signaling that induce a spectrum of signaling activities inside the cell—including one that decouples blood stem cell proliferation and differentiation.