Figure 2

Structural and physicochemical impact of CDKL1 amino acid changes.

(A) Molecular position of CDKL1 amino acids Cys¹⁴³, Ser²⁰⁶, and Thr¹³⁵ in relation to conserved sequence motifs and accessible surfaces. CDKL1 amino acids 1–303 are shown (AlphaFold AF-Q00532-F1-model_v4; AlphaFill AF-Q00532-F1-model_v1). Different colors in the ribbon representation (left model) and on the protein surface (right model) indicate conserved sequence motifs in the protein kinase domain of CDKL1 (amino acids 5–288). Secondary structure elements including β4, β6, and β7 strands as well as αC, αE, αF, and αG helices are indicated. (B) Conservation of CDKL1. Conservation was determined between 150 sequences among various species and visualized using the ConSurf server. Conserved amino acids are highlighted in maroon and variable residues in cyan. Cys¹⁴³, Ser²⁰⁶, and Thr¹³⁵ are marked with arrowheads. (C) Structural or physicochemical consequences of CDKL1 amino acid changes. Ribbon representations show spatial positions of CDKL1 wild-type amino acids Cys¹⁴³ and Thr¹³⁵ (top models) and exchanged amino acids Arg¹⁴³ and Met¹³⁵ (bottom models) as well as neighboring amino acids and phosphate donor ATP (all as sticks). Van der Waals (VDW) overlaps ≥0.4 Å (i.e., contacts) are shown as green lines; VDW overlaps ≥0.6 Å (i.e., clashes) are indicated by magenta lines. Side chains are colored by element (hydrogen: white; carbon: gray; oxygen: red; nitrogen: blue; sulfur: yellow; phosphorus: orange). In the ribbon representations for the p.Thr135Met change, amino acids involved in ATP positioning and protein catalysis are indicated by dark blue and light blue, respectively. Protein surface models show surface hydrophobicity of wild-type amino acid Ser²⁰⁶ (top model) and replaced amino acid Leu²⁰⁶ (bottom model), both within the putative Gly-Lys-Ser-Asp-Val-Asp protein binding motif. The color code ranges from cyan for the most hydrophilic residues to tan for the most hydrophobic residues. Comprehensive models are shown in Supplemental Figures 2–4.