Fig. 6.

Computational docking and models for lipid binding by IDE. (A) Binding site clusters for Ins(1,3)P2 computationally docked to IDE, with the ligands drawn as stick figures. The site that possibly mediates interaction with membrane-bound PtdIns head groups is indicated by the red circle. The site that may mediate the head group interaction with activating lipid bound within the substrate-binding chamber is circled in black. Side chains of active site residues are shown in a stick representation. (B) A model for the interaction with membrane-bound PtdIns(3)P with the lipid in a space-filling representation and the protein in a ribbon representation. The lipid is shown with 17:0 and 20:4 acyl chains and was placed manually so that its head group matches the binding of Ins(1,3)P2, indicated by the red circle in A. Side chains of active site residues are shown. (C) Space-filling view of the IDE surface that would interact with the membrane in the model shown in B. Residue atoms were colored based on conservation using the ConSurf server, with blue the least conserved and dark red the most conserved. The conservation of this surface is the highest for the any external surface of IDE. (D) A model for the internal binding of PtdIns(3)P with the lipid head group manually placed to match the binding of Ins(1,3)P2 in the docking cluster indicated by the black circle in A. The lipid is shown with 17:0 and 20:4 acyl chains. (E) Cutaway view of the IDE substrate-binding chamber showing another view of the bound PtdIns(3)P model to emphasize the ability of the inner chamber to accommodate the lipid. (F) Cutaway view of the substrate-binding chamber showing the surface that would interact with PtdIns acyl chains in the model shown in D and E. The surface is color-coded by electrostatic potential using the adaptive Poisson–Boltzmann solver server with cutoffs of ±10 kT. The surface proposed to interact with the acyl chains has a relatively low electrostatic potential, consistent with this interaction.