Fig. 3: Structure of autoinhibited ABL1 showing locations of patient missense variants. | European Journal of Human Genetics

Fig. 3: Structure of autoinhibited ABL1 showing locations of patient missense variants.

From: Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity

Fig. 3

a Cartoon representation of autoinhibited ABL1 in complex with ATP-competitive inhibitor PD166326 and the myristoyl group of a myristoylated peptide (both shown in stick representation), with side-chains of patient missense variants shown as purple spheres (PDB: 1OPL). b Closeup view showing that the Tyr245 side-chain packs in a hydrophobic crevice formed by the side-chains of Lys313 and Pro315 of the kinase ___domain. Substitution with a cysteine would abolish phosphorylation at this site and may disrupt an important salt bridge between Lys313 and Glu117. c Closeup view showing that Ala356, Ala452, Val525 and Glu528 cluster at the myristoyl-binding pocket and form important hydrophobic interactions with the myristoyl group and to other amino acids that complete the binding pocket. Amino acid substitutions observed in patients at these sites are likely to impact binding of the myristoylated peptide.

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