FVIII/VWF-D′D3 form an extended interface of van der Waals interactions. (A) VWF-TIL′ (red) exhibits shape complementarity to FVIII, C1 (cyan), and A3 (violet) domains shown in surface rendering. Insertion of the VWF-TIL′ N terminal residue in a shallow pocket in the A3 domain can be seen. (B) VWF-TIL′/FVIII interacting residues, outside of the a3 peptide, shown as sticks, colored as in panel A. Residues labeled in red have known disease-causing mutations. (C) Docking solution of VWF-D3 indicates C8-3 subdomain (orange) is in close contact with the FVIII C2 domain (teal), with hydrophobic spike residues in FVIII-C2 shown as sticks. (D) The calcium-binding site of VWF-D3 VWD3 subdomain (orange) is in close proximity to the FVIII C1 domain (cyan).