Conformational changes of the ET3i C2 domain and hemophilia A–associated mutations that decrease VWF binding. (A) Structural superposition of the unbound ET3i structure with ET3i in the 2A9 antibody complex. Arrow indicates swivel-like movement of the C2 domain (light gray, ET3i alone structure) (PDBID#, 6MF0). (B) Ribbon diagram representation of hemophilia A–associated mutations known to decrease VWF binding, represented by spheres (yellow, adjacent to 2A9 epitope; red, proximal to 2A9 epitope; green, opposing face of 2A9 epitope). (C) Van der Waals sphere representation of the fVIII C1 domain, highlighting the solvent exposure of hemophilia A–associated mutations.