Fig. 8: Conformations and solvent accessibility of IDH1 WT, R132Q, and R132H upon substrate binding. | Nature Communications

Fig. 8: Conformations and solvent accessibility of IDH1 WT, R132Q, and R132H upon substrate binding.

From: Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms

Fig. 8

Helices displaying profound differences in alignment of the three forms of IDH1 are highlighted. The seatbelt feature is indicated on the α11 and α9 helices. A Binary WT:NADP(H)13 collapses to a closed conformation upon ICT binding, though moderate levels of deuterium exchange are still permitted. B Binary R132Q:NADP(H) collapses to a closed conformation upon ICT binding, showing improved catalytic efficiency for the conventional reaction and lower deuterium uptake compared to R132H. However, catalytic activity is much lower compared to WT. C Binary R132H:NADP(H)30 collapses to a fully closed conformation only upon αKG binding14, but a seatbelt is not formed and deuterium uptake remains high. D Binary R132Q:NADP(H) forms semi-closed and closed conformations upon binding αKG and NADP-αKG, respectively, with a seatbelt successfully formed in the closed state in some of our crystallographic snapshots. The αKG binding site was shifted away from the α9 helix, though catalytic activity was much higher than that seen in R132H.

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