Hotspot Mutations in KIT Receptor Differentially Modulate Its Allosterically Coupled Conformational Dynamics: Impact on Activation and Drug Sensitivity
Figure 6
A-loop conformations in KITWT and KITD816H/V/Y/N mutants.
(a) Cluster analysis of the MD conformations picked every 10 ps over the 96 ns of productive MD simulations were performed on the RMSDs computed for only the A-loop backbone atoms. Five different sets were produced through 5 independent runs of clustering (I–V). The composition of clusters is represented as colored barplots in a logarithmic scale: KITWT (gray), KITD816V (red) KITD816H (green), KITD816Y (blue), KITD816N (pink). The rank in the concatenated trajectory of the corresponding reference structure is reported in the bottom of each barplot and colored accoring to the population of the group (see below). (b–d). Superposition of the reference structures in each cluster analysis run. The reference structures are drawn as cartoons illustrating the A-loop conformation (b), the relative orientation of the residues Y823 (A-loop) and D792 (C-loop) (c) and the conformation of DFG motif (A-loop) (d). The A-loop is shown as cartoon diagrams, residues Y823 and D792 as sticks, F811 as thick lines; D/H/V/Y/N816 as sphere. The H-bonds are shown by dotted lines. The A-loop conformations observed in all simulated proteins including KITWT are shown in grey; conformations detected in all protein but one mutant are distinguished in black or blue; conformations detected only in the mutants are in yellow; the proper conformations of KITD816V mutant are in red; characteristic of the pair of mutants, KITD816V/Y or KITD816V/N are in purple or in pink.