PDB 1V7N deposited: 2003-12-18 modified: 2009-02-24
Title Human Thrombopoietin Functional Domain Complexed To Neutralizing Antibody TN1 Fab
Authors Feese, M.D., Hirose, M., Kato, T., Kato, Y., Kuroki, R., Maeda, Y., Matsukura, Y., Matsumoto, A., Miyazaki, H., Muto, T., Ogami, K., Shigematsu, H., Tahara, T., Tamada, T., Watarai, H.
Structure factors resolution 3.3 rfactor 0.16708 rfree 0.30477
DPI 1.57 theoretical min: 0.86
Related PDB Entries 1V7M

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.

Proc.Natl.Acad.Sci.USA 2004 Feb; 101(7):1816-1821 doi:10.1073/pnas.0308530100

Cross References
Database source Identifier Description
PubMed 14769915 PNASA6
PubMed 11976502 ABCRE6
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
1V7N/1 1V7N 1 trimer 0 3 0 3996
1V7N/2 1V7N 2 trimer 0 3 0 3975
1V7N/3 1V7N 3 trimer 0 3 0 3971
1V7N/4 1V7N 4 trimer 0 3 0 3902