7A6O

Crystal Structure of the Complex of the Recombinant Von Willebrand Factor AIM-A1 domain and VHH81 at 2.1 Angstrom resolution

7A6O の概要

• エントリーDOI: 10.2210/pdb7a6o/pdb
• 分子名称: von Willebrand factor, VHH81 Nanobody fragment, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: thrombosis von willebrand factor a1 aim-a1 blood clotting complex vwf, blood clotting
• 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: 37399.70

構造登録者

Brown, A.K.,Emsley, J. (登録日: 2020-08-25, 公開日: 2021-03-03, 最終更新日: 2024-01-31)

主引用文献

Arce, N.A.,Cao, W.,Brown, A.K.,Legan, E.R.,Wilson, M.S.,Xu, E.R.,Berndt, M.C.,Emsley, J.,Zhang, X.F.,Li, R.
Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module.
Nat Commun, 12:2360-2360, 2021

PubMed Abstract: Von Willebrand factor (VWF) activates in response to shear flow to initiate hemostasis, while aberrant activation could lead to thrombosis. Above a critical shear force, the A1 domain of VWF becomes activated and captures platelets via the GPIb-IX complex. Here we show that the shear-responsive element controlling VWF activation resides in the discontinuous autoinhibitory module (AIM) flanking A1. Application of tensile force in a single-molecule setting induces cooperative unfolding of the AIM to expose A1. The AIM-unfolding force is lowered by truncating either N- or C-terminal AIM region, type 2B VWD mutations, or binding of a ristocetin-mimicking monoclonal antibody, all of which could activate A1. Furthermore, the AIM is mechanically stabilized by the nanobody that comprises caplacizumab, the only FDA-approved anti-thrombotic drug to-date that targets VWF. Thus, the AIM is a mechano-regulator of VWF activity. Its conformational dynamics may define the extent of VWF autoinhibition and subsequent activation under force.

PubMed: 33883551
DOI: 10.1038/s41467-021-22634-x

実験手法

X-RAY DIFFRACTION (2.117 Å)