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|1v7m, resolution 2.51Å ()|
Human Thrombopoietin Functional Domain Complexed To Neutralizing Antibody TN1 Fab
The cytokine thrombopoietin (TPO), the ligand for the hematopoietic receptor c-Mpl, acts as a primary regulator of megakaryocytopoiesis and platelet production. We have determined the crystal structure of the receptor-binding domain of human TPO (hTPO(163)) to a 2.5-A resolution by complexation with a neutralizing Fab fragment. The backbone structure of hTPO(163) has an antiparallel four-helix bundle fold. The neutralizing Fab mainly recognizes the C-D crossover loop containing the species invariant residue Q111. Titration calorimetric experiments show that hTPO(163) interacts with soluble c-Mpl containing the extracellular cytokine receptor homology domains with 1:2 stoichiometry with the binding constants of 3.3 x 10(9) M(-1) and 1.1 x 10(6) M(-1). The presence of the neutralizing Fab did not inhibit binding of hTPO(163) to soluble c-Mpl fragments, but the lower-affinity binding disappeared. Together with prior genetic data, these define the structure-function relationships in TPO and the activation scheme of c-Mpl.
Structure of the receptor-binding domain of human thrombopoietin determined by complexation with a neutralizing antibody fragment., Feese MD, Tamada T, Kato Y, Maeda Y, Hirose M, Matsukura Y, Shigematsu H, Muto T, Matsumoto A, Watarai H, Ogami K, Tahara T, Kato T, Miyazaki H, Kuroki R, Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1816-21. Epub 2004 Feb 9. PMID:14769915
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[TPO_HUMAN] Defects in THPO are the cause of thrombocythemia type 1 (THCYT1) [MIM:187950]. A myeloproliferative disorder characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications.
[TPO_HUMAN] Lineage-specific cytokine affecting the proliferation and maturation of megakaryocytes from their committed progenitor cells. It acts at a late stage of megakaryocyte development. It may be the major physiological regulator of circulating platelets.
About this Structure
- Feese MD, Tamada T, Kato Y, Maeda Y, Hirose M, Matsukura Y, Shigematsu H, Muto T, Matsumoto A, Watarai H, Ogami K, Tahara T, Kato T, Miyazaki H, Kuroki R. Structure of the receptor-binding domain of human thrombopoietin determined by complexation with a neutralizing antibody fragment. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1816-21. Epub 2004 Feb 9. PMID:14769915 doi:10.1073/pnas.0308530100
- Kuroki R, Hirose M, Kato Y, Feese MD, Tamada T, Shigematsu H, Watarai H, Maeda Y, Tahara T, Kato T, Miyazaki H. Crystallization of the functional domain of human thrombopoietin using an antigen-binding fragment derived from neutralizing monoclonal antibody. Acta Crystallogr D Biol Crystallogr. 2002 May;58(Pt 5):856-8. Epub 2002, Apr 26. PMID:11976502