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. 2020 Nov 20;9:e59704. doi: 10.7554/eLife.59704

Figure 1. Modelling of proposed VRAC inhibitors on the Cryo-EM structure of LRRC8 channels.

(A) Two orthogonal views: a side view with two chains removed from the hexameric LRRC8A protein with bound DCPIB and a top view for the hexameric VRAC channel (PDB:6NZW). (B, D–I) Docked VRAC inhibitors (orange) in the VRAC Arg103 extracellular selectivity filter. Protein surface coloured according to electrostatics: electronegative (red), electropositive (blue), and electroneutral (white). (B) MM/GBVI binding energies of docked DCPIB (orange) in VRAC (−5.2 kcal mol−1) in a side view superimposed on the cryo-EM DCPIB pose (black). (C) Top-view of cryo-EM pose of DCPIB (black) in VRAC. (D) Flufenamic acid (−5.1 kcal mol−1) (E) Mefenamic acid (−5.2 kcal mol−1) (F) MONNA (−5.8 kcal mol−1) (G) NS3728 (−6.4 kcal mol−1) (H) 4-sulfonic calix[6]arene (−9.9 kcal mol−1) (I) Tamoxifen (−6.5 kcal mol−1).

Figure 1.

Figure 1—figure supplement 1. Further modelling of VRAC inhibitors.

Figure 1—figure supplement 1.

(A) Top view and (B) side view of the cryo-EM structure of DCPIB in the arginine pore of VRAC (C–I). Molecular surfaces coloured by electrostatic potential for the docked poses of VRAC inhibitors, indicating regions of negative (red) and positive (blue) potential. (C) Cryo-EM pose of DCPIB. Docked poses of (D) Flufenamic acid (E) Mefenamic acid (F) MONNA (G) NS3728 (H) 4-sulfonic calix[6]arene and (I) tamoxifen.