Figure 5From: Structural effects of clinically observed mutations in JAK2 exons 13-15: comparison with V617F and exon 12 mutationsPossible origins of V617X mutational effects derived from the snapshots of various mutant simulations at 44 ns. Color codes are the same as in Figure 1. In wild-type JAK2 (WT), the JH1 activation loop is in contact with V617 and nearby residues, as well as the residues of the JH2 C-helix (especially F595 and S591). V617C is very similar to WT. All key interactions seem to be kept. However, C617 binds to different parts of the JH1 activation loop: it is now close to K1005 rather than L1001 and P1002. K1005 is the edge of the red region shown in the figure. V617I is similar to V617C and WT in that I-2 and I-3 are maintained (i.e., the JH1 activation loop is locked by the JH2 C-helix and residues in the V617 region). However, the bulky side chain of I617 pushes the JH1 activation loop toward the I-1 interface (JH1 C-helix/JH2 C-helix) and breaks the I-1 interactions. In V617F, F617 interacts with F595 and hence blocks the contacts between the JH1 activation loop and the JH2 C-helix. The JH1 activation loop is wide-open and highly accessible. In V617Y, Y617 also interacts with F595 and blocks the contacts between the JH1 activation loop and the JH2 C-helix. However, the polar tail of Y617 moves near the interface between the JH1 C-helix and the JH2 C-helix, forming multiple hydrogen-bonds with nearby water molecules and the JH1 activation loop (not shown). The result is that the JH1/JH2 interface is not as open as in the case of V617F.Back to article page