Model of the factor VIII and factor IXa molecules. Shown are representiations of porcine factor IXa (Protein Data Bank accession code 1pfx) and the triplicated A-domains of human factor VIII (Hemophilia A web site, http://europium.mrc.rpms.ac.uk), which are derived from crystallography and homology modeling, respectively. Factor IXa binding region in the factor VIII A3 domain (residues 1811-1818) is shown in white, whereas the binding regions in the A2 domain (residues 558-565 and 698-710) are shown in dark and light blue, respectively (space-filling representations). These sites are in close vicinity, and are exposed at the same side of the molecule. The factor VIII A2 domain is required to induce significant changes within the factor IXa protease domain, indicating that it binds to the factor IXa protease domain. The A3 domain of factor VIII has been proposed to interact with the factor IXa light chain. Within the factor IXa light chain, residues 12, 64, 69, 78, 92, and 94 (see refs 150 to 155) are indicated (red, space-filling representation). These residues have been reported to be associated with an abnormal response to factor VIIIa in factor X activation.