Extended Data Fig. 2: Structures illustrating potential interactions between IDH2 second-site mutations and enasidenib.

a–h, Detailed view of the interactions between wild-type IDH2 Q316 (a, e) and Q316’ (c, g) or mutant IDH2(Q316E) (b, f) and IDH2(Q316E’) (d, h) with AG-221 in the predicted dominant conformation (a–d) or a minor conformation (e–h). Hydrogen bonds are depicted in light green. Note the disrupted hydrogen bond (depicted as orange bar) in d resulting from the Q316E mutation in the IDH2’ subunit. i–p, Detailed view of the interactions between wild-type IDH2 I319 (i, m) and I319’ (k, o) or mutant IDH2(I319M) (j, n) and IDH2(I319M’) (l, p) with AG-221 in the predicted dominant conformation (i–l) or a predicted minor conformation (m–p). The solvent-excluded surface of AG-221 is shown transparently in grey. The van der Waals radius of the Cδ1 and Cγ2 atoms of I319/I319’ or the Sδ and Cε atoms of I319M/I319M’ are depicted as spheres. Unfavourable steric interactions between AG-221 and these atoms are depicted in red. Throughout the figure, the IDH2 subunit is depicted in blue-grey, the IDH2’ subunit in purple, and AG-221 in teal. Non-polar hydrogen atoms are not shown. White, red, blue and yellow portions of stick structures indicate hydrogen, oxygen, nitrogen and sulfur atoms, respectively. All models were based on the AG-221–IDH2 structure (PDB code 5I96)⁹ (see Methods).