Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis

The thrombopoietin-MPL axis plays essential roles in hematopoietic stem cell biology and platelet production. Cryo-EM structure of the dimeric thrombopoietin- MPL receptor complex enabled design of biased agonists that tune intracellular signaling, thereby uncoupling the primary opposing functions of thrombopoietin signaling, hematopoietic stem cell maintenance, and differentiation.

Naotaka Tsutsumi,1,2,3,4,* Zahra Masoumi,5 Sophie C. James,5 Julie A. Tucker,5 Hauke Winkelmann,6 William Grey,5 Lora K. Picton,1 Lucie Moss,5 Steven C. Wilson,1,2 Nathanael A. Caveney,1,2 Kevin M. Jude,1,2,3 Cornelius Gati,2,7 Jacob Piehler,6 Ian S. Hitchcock,5,* and K. Christopher Garcia1,2,3,8,*
¹Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA

²Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
³Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
⁴Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan
⁵York Biomedical Research Institute, Department of Biology, University of York, Heslington, York YO10 5DD, UK
⁶Department of Biology/Chemistry and Center of Cellular Nanoanalytics, Osnabru ̈ ck University, 49076 Osnabru ̈ ck, Germany
⁷Biosciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA
⁸Lead contact
*Correspondence: [email protected] (N.T.), [email protected] (I.S.H.), [email protected] (K.C.G.)