7EOW

High-resolution structure of vWF A1 domain in complex with caplacizumab, the first nanobody-based medicine

7EOW の概要

• エントリーDOI: 10.2210/pdb7eow/pdb
• 分子名称: von Willebrand factor, caplacizumab (3 entities in total)
• 機能のキーワード: vwf, vfw a1, caplacizumab, nanobody, structural protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 41567.22

構造登録者

Lee, H.T.,Heo, Y.-S. (登録日: 2021-04-23, 公開日: 2021-07-07, 最終更新日: 2024-11-13)

主引用文献

Lee, H.T.,Park, U.B.,Jeong, T.J.,Gu, N.,Lee, S.H.,Kim, Y.,Heo, Y.S.
High-resolution structure of the vWF A1 domain in complex with caplacizumab, the first nanobody-based medicine for treating acquired TTP.
Biochem.Biophys.Res.Commun., 567:49-55, 2021

PubMed Abstract: von Willebrand factor (vWF) is a huge oligomeric glycoprotein involved in blood homeostasis. However, this protein is also implicated in acquired thrombotic thrombocytopenic purpura (TTP). The blocking of its binding with platelets has been recognized as an attractive therapeutic strategy for treating acquired TTP. Caplacizumab, a bivalent single-domain antibody (VHH), is the first FDA-approved nanobody drug against vWF for the treatment of acquired TTP. Here, we describe the crystal structure of the A1 domain of vWF in complex with the caplacizumab nanobody at the resolution of 1.60 Å. This structure elucidates the precise epitope and binding mode of caplacizumab. Unexpectedly, caplacizumab binds to the bottom face of the vWF A1 domain and does not create any steric clash with platelet-receptor glycoprotein Ib (GPIb) bound to vWF. However, its binding can stabilize the different conformation within the N-terminus and α1β2 loop from the GPIb bound structure, suggesting that the mechanisms of caplacizumab would not be the direct competition of GPIb binding to vWF A1 domain but the conformational arrestment of vWF in an inappropriate state to platelet adhesion. This high-resolution structure would provide helpful information for the design of improved anti-vWF therapeutics for the treatment of acquired TTP.

PubMed: 34144500
DOI: 10.1016/j.bbrc.2021.06.030

実験手法

X-RAY DIFFRACTION (1.6 Å)