Exploring the dynamic mechanism of allosteric drug SHP099 inhibiting SHP2E69K

Study on the allosteric activation mechanism of SHP2 via elastic network models and neural relational inference molecular dynamics simulation

“…11 There is a long loop (E83-S118) containing allosteric site 1 at the junction of N-SH2 and C-SH2, as well as G207-R220 in the C-tail, both of which have higher molecular flexibility. 68…”

“…6A, the N-SH2/C-SH2 domain can also be subdivided into eight parts: N-aA (S3-V25), which supports N-SH2 conformational stability; three evolutionarily conserved b-sheets N-3b (D26-I56); N-loop (Q57-T65), consisting of the D'E-loop and EF-loop, where the D'E-loop is inserted into the PTP catalytic pocket to prevent substrate entry; N-aB (Y66-C105) containing allosteric site 2 (Q79-Q87); C-aA (A105-H132) containing allosteric site 1 (T108-W112); 67 three evolutionarily conserved b-sheets C-3b (G133-L177); C-aB (K178-K198) whose T191/V194 strongly interacts with allosteric site 1, contributing to the structural rigidity of N-SH2/C-SH2. 68 The C-tail (K199-R220) is responsible for linking C-SH2 to PTP, in which T219 and R220 are both key residues that cause SHP2 allosterism. 67 It is worth mentioning that there are two phosphorylated active sites (i.e., R32 and R148) in N-3b and C-3b, for the localization and recognition of the ITIM/ITSM phosphopeptide in the tail of PD-1.…”

“…11 There is a long loop (E83-S118) containing allosteric site 1 at the junction of N-SH2 and C-SH2, as well as G207-R220 in the Ctail, both of which have higher molecular flexibility. 68 Fig. S3A (ESI †) shows the root mean square deviation (RMSD) values of the main chain atoms to monitor the fluctuations of the protein relative to the initial structure; the larger the RMSD value, the greater the range of motion of the system, and the smaller the spatial site resistance of the system.…”

Engineering SHP2 Phosphatase for Optical Control

“…Light-induced decaging will restore the active site and thus restore phosphatase activity. Constitutive activation of SHP2 through generation of the E69K mutant will decouple the protein from growth factor-induced upstream signaling . This mutant was used for all further experiments unless noted otherwise.…”