Structure of the A1/GpIbα complex. (A) Three-dimensional representation of the VWF A1 domain/GpIbα complex derived from PDB-deposit 1M1O.³² N- and C-terminal flanking peptide (N-AIM and C-AIM) are colored in purple and orange, respectively; 1 and 2 refer to interactive sites 1 and 2, respectively. Figure was generated using PyMOL software. (B) Three-dimensional representation of the A1 domain in complex with VHH81 (a sequence identical analog of caplacizumab; pale green) derived from PDB-deposit 7A6O.³³ VHH81/caplacizumab stabilizes the conformation of the N-AIM/C-AIM interaction, thereby preventing binding of GpIbα to interactive site 2. Figure was generated using PyMOL software. (C) Two-dimensional representation of the A1 domain. Circles indicate positions of residues where mutations have been associated with increased GpIbα binding in patients with von Willebrand disease-type 2B. Squares indicate positions of residues where mutations have been associated with reduced GpIbα binding in patients with von Willebrand disease-type 2M. Note, in the 3-dimensional space, the N- and C-terminal ends of the A1 domain are in close vicinity via a disulfide bridge between Cys¹²⁷² and Cys¹⁴⁵⁸.