8G04
Structure of signaling thrombopoietin-MPL receptor complex
Summary for 8G04
| Entry DOI | 10.2210/pdb8g04/pdb |
| EMDB information | 29644 |
| Descriptor | Thrombopoietin, Thrombopoietin receptor, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total) |
| Functional Keywords | tpo, tpor, cytokine, receptor, signaling, haematology |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 163776.40 |
| Authors | Tsutsumi, N.,Jude, K.M.,Gati, C.,Garcia, K.C. (deposition date: 2023-01-31, release date: 2023-08-30, Last modification date: 2024-11-06) |
| Primary citation | Tsutsumi, N.,Masoumi, Z.,James, S.C.,Tucker, J.A.,Winkelmann, H.,Grey, W.,Picton, L.K.,Moss, L.,Wilson, S.C.,Caveney, N.A.,Jude, K.M.,Gati, C.,Piehler, J.,Hitchcock, I.S.,Garcia, K.C. Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis. Cell, 186:4189-4203.e22, 2023 Cited by PubMed Abstract: Thrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 Å resolution cryoelectron microscopy structure of the extracellular TPO-TPO receptor (TpoR or MPL) signaling complex, revealing the basis for homodimeric MPL activation and providing a structural rationalization for genetic loss-of-function thrombocytopenia mutations. The structure guided the engineering of TPO variants (TPO) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. Partial agonist TPO decoupled JAK/STAT from ERK/AKT/CREB activation, driving a bias for megakaryopoiesis and platelet production without causing significant HSC expansion in mice and showing superior maintenance of human HSCs in vitro. These data demonstrate the functional uncoupling of the two primary roles of TPO, highlighting the potential utility of TPO in hematology research and clinical HSC transplantation. PubMed: 37633268DOI: 10.1016/j.cell.2023.07.037 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.4 Å) |
Structure validation
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