1V7N

Human Thrombopoietin Functional Domain Complexed To Neutralizing Antibody TN1 Fab

Summary for 1V7N

• Entry DOI: 10.2210/pdb1v7n/pdb
• Related: 1V7M
• Descriptor: Monoclonal TN1 Fab Light Chain, Monoclonal TN1 Fab Heavy Chain, Thrombopoietin, ... (4 entities in total)
• Functional Keywords: thrombopoietin, fab fragment, complex (cytokine-antibody), immune system-cytokine complex, immune system/cytokine
• Biological source: Mus musculus (house mouse); More
• Cellular location: Secreted: P40225
• Total number of polymer chains: 12
• Total formula weight: 256850.25

Authors

Feese, M.D.,Tamada, T.,Kato, Y.,Maeda, Y.,Hirose, M.,Matsukura, Y.,Shigematsu, H.,Kato, T.,Miyazaki, H.,Kuroki, R. (deposition date: 2003-12-18, release date: 2004-03-02, Last modification date: 2024-10-09)

Primary citation

Feese, M.D.,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.USA, 101:1816-1821, 2004

PubMed Abstract: 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.

PubMed: 14769915
DOI: 10.1073/pnas.0308530100

Experimental method

X-RAY DIFFRACTION (3.3 Å)