Extended Data Fig. 3: Inhibitor and substrate binding and V74W^MPC2 variant.

a, Chemical structures of select MPC inhibitors and their IC₅₀ values. b-d, MPC’s binding pocket for UK5099, AKOS, and GW604714X. The slab view of MPC is shown (colored by electrostatic potential). e, Structural comparison of MPC in complex with pyruvate and UK5099. The pyruvate is colored in purple and UK5099 is colored in light pink. f-g, Docking of compound 2 and 12 (ref. ¹¹) in MPC, compared to the experimental pose of AKOS. The AKOS is coloured in light orange, and the other inhibitors are coloured in gray. h, Effect of V74W^MPC2 substitution on the yeast growth. The yeasts are grown on the synthetic defined medium that lacks leucine and valine (SD-L-V). WT, wild type; EV, empty vector. i-l, Known substrates (i, acetoacetate; j, beta-hydroxybutyrate; k, dichloroacetate; l, 2-chloroacetate) modelled in the substrate binding-pocket of MPC. Substrate molecules were placed in the pocket by aligning with the pyruvate. Pyruvate and other substrates are shown as sticks in purple and yellow, respectively. m, Structural comparison of MPC that was bound with UK5099 and GW604714X, respectively. The MPC in complex with UK5099 was shown in grey. For the MPC complexed with GW604714X, its two subunits, MPC1 and MPC2, are colored in green and cyan, respectively.