1. Introduction
Gastrointestinal stromal tumors (GISTs) are the most common primary
mesenchymal tumors of the human gastrointestinal tract, and most GISTs express
constitutively activated c-Kit oncoproteins.1 Several clinical studies demonstrate that
tumors showing mutation in exon 11 (encoding the juxtamembrane domain) respond
better than all the other GIST tumoral genotypes. The KIT wild-type sequence folds
into a series of β- hairpin structures. The structure, stability and folding of β- hairpin
structures has been the object of many studies. Recently, several works reported
successful simulations of reversible hairpin folding of different peptides in explicit
water at native folding conditions through self-guided molecular dynamics (SGMD)
simulations.2
2. Results and Discussion
Using SGMD simulations we study the reversible
folding events of wild-type and mutated c-Kit JMX
domains. The mutations considered were the two-residue
deletion Δ559-560 (Fig.1) and the missense point mutation
V560G, both known to constitutively activate c-Kit in
GISTs. This work aids to support the clinical evidence of a
better response to Imatinib, an ATP-competitive TKIs, of
KIT exon 11 mutant in comparison with WT receptor and
provides the first atomistic description of the output of
several clinical studies of GIST treated with Imatinib.
