Most common FBXW7 mutations in CLL lead to structural changes in hotspot substrate binding areas resulting in different hydrophobicity and electrostatic interactions. (A) FBXW7 ribbon structure depicting α-helical and β-sheet structures. WD40 domain highlighted in green. (B) Magnification of panel (A) of amino acid residues 423 (black), 425 (purple), 465 (gray), 479 (blue), 503 (yellow), and 505 (red). (C) Partial view from the midpoint of the structure (see black line and arrowheads in panel B) reveals side-chain protrusions of these amino acid residues into the center of the circular β-sheet configuration. Most common mutations cause changes of (D) hydrophobicity and (E) electrostatic surfaces. In panel D, red indicates hydrophobic surfaces; blue, hydrophilic surfaces. In panel E, red indicates negative electrostatic surfaces; blue, positive electrostatic surfaces.