Fig. 3

Structural analysis of the G724S variant. (A) An overall view of the NTRK1 protein in its inactive conformation (PDB: 4GT5). The two lobes, N- and C-terminal are labeled and colored with green (C-lobe) and grey (N-lobe). Hinge connecting both lobes (blue), the activation loop (yellow), the DGF motif (orange), and the HDR catalytic residues (magenta) are shown. G724 (red asterisk) is shown in stick representation. (B) Closeup view of 724 position and alignment of structures (< 1Å RMSD) containing various substitutions at this position: Ala (yellow, PDB: 5E1S), Cys (cyan, PDB: 7FEH), active form of NTRK1 (orange, PDB: 5JFX), inactive NTRK1 (green, PDB: 4GT5), and Alphafold predicted model of Ser at 724 (blue). Shown in stick representation are L601, L597, and T653, which form a hydrophobic core. (C) Closeup view of the kinase core of G724S mutant showing the polar network (dashed lines) that regulates conformational switches. W693 and P727 π-packing is shown (blue dashed line). 724 S is modeled in two conformations (blue and green). Red crosses represent water molecules found in the crystal structure (PDB: 4GT5). 724 S may interfere with the closest residues R602, N598 (N), and T653 (T) of the catalytic loop