4R9W

Crystal structure of platelet factor 4 complexed with fondaparinux

4R9W の概要

• エントリーDOI: 10.2210/pdb4r9w/pdb
• 関連するPDBエントリー: 4R97 4R9Y
• 関連するBIRD辞書のPRD_ID: PRD_900028
• 分子名称: Platelet factor 4, 2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-beta-D-glucopyranuronic acid-(1-4)-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-methyl 2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranoside (3 entities in total)
• 機能のキーワード: pf4, fondaparinux, cxc chemokine, platelet factor, glycosaminoglycan, platelet, cytokine
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 17072.65

構造登録者

Cai, Z.,Zhu, Z.,Liu, Q.,Greene, M.I. (登録日: 2014-09-08, 公開日: 2015-12-16, 最終更新日: 2024-11-20)

主引用文献

Cai, Z.,Yarovoi, S.V.,Zhu, Z.,Rauova, L.,Hayes, V.,Lebedeva, T.,Liu, Q.,Poncz, M.,Arepally, G.,Cines, D.B.,Greene, M.I.
Atomic description of the immune complex involved in heparin-induced thrombocytopenia.
Nat Commun, 6:8277-8277, 2015

PubMed Abstract: Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the 'open' end of the tetramer. Fondaparinux and KKO thereby collaborate to 'stabilize' the ternary pathogenic immune complex. Binding of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. The atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.

PubMed: 26391892
DOI: 10.1038/ncomms9277

実験手法

X-RAY DIFFRACTION (2.5 Å)