Functional study of the aromatic residues in the small-XXX-small motifs of the loop sequence in VKOR. (A) Multiple sequence alignment of VKOR near the small-XXX-small motifs of the loop sequence. Amino acid sequences of VKOR from widely divergent species were aligned by CLUSTAL W. Conserved aromatic residues are indicated by numbers according to the position of amino acid residues in the human VKOR sequence. (B) Cell-based activity assay of the aromatic residue mutants of VKOR. (C) Warfarin-resistance study of the aromatic residue mutants of VKOR, performed as described in the legend for Figure 5. (D) Normalized warfarin resistance of the aromatic residue mutants of VKOR. Warfarin sensitivity of wild-type VKOR was normalized to 1. Warfarin resistance, as determined by IC₅₀, is available in supplemental Table 2.