X-ray structure of MAA868 Fab in complex with FXI CD. (A) Ribbon representation of the MAA868 Fab–FXI CD complex structure (green and yellow with gray) in superposition with a published FXI zymogen structure (PDB 2F83)²²  is shown. The apple domains of FXI, which were not part of the MAA868 Fab–FXI CD complex, are shown in yellow. The activation cleavage site and active site location are indicated by arrows, showing that MAA868 binds close to the active site but away from the activation cleavage site (see also supplemental Figure 2). (B) MAA868 Fab binding site on FXI is shown. Parts of the heavy and light chains that make close contacts with FXI are shown as ribbons. The catalytic domain is shown as gray surface, and the side chains of selected amino acid residues are shown including residues of the catalytic triad. In addition, the heavy chain loops CDR1 (magenta), CDR2 (green), and CDR3 (red) are shown. Y145 and R144 are shown with their side chains (see text). (C) Fab-bound CD conformation shares structural similarities with the inactive CD in the zymogen structure (PDB 2F83). Compared with the free CDa structure (left panel), S1 pocket is not formed in either the Fab bound CDa structure (middle panel) or the free CDz structure (right panel). Three crucial loops near the active site that are all disordered in the free CDz structure (right panel) are either shifted (220 and 145 loop) or also disordered (186 loop) in the Fab complex (middle panel).