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. 2018 Jan 17;7:82. [Version 1] doi: 10.12688/f1000research.13167.1

Figure 4. Graphic representation of the V617F-activation mechanism in Janus kinase2 (JAK2).

Figure 4.

The V617F activation has been suggested to derive from a combination of several molecular events triggered from a region surrounding the JH2 αC but also involving the SH2-JH2 linker. Phenylalanine 617 interacts with F594 and F595 from the JH2 αC and F537 from the SH2-JH2 linker, as supported by structural data 9, 159, then induces putative conformational changes that are transmitted to the adjacent catalytic kinase domain where activation is initiated. Targeting the ATP-binding pocket of JH2 that is spatially close the αC represents an appealing approach for specific targeting of the mutant JAK2V617F. Small molecules, such as BI-D1870 (as represented here 160), have been co-crystallized as bound to the JH2 ATP-binding site. The use of amendable compounds targeting the JH2 pocket has recently become a tantalizing concept and will represent the future challenge for drug design.