Figure 2.

Location of the assigned pore binding site of lopinavir in the hERG cryo-EM structure and the closely related Dickson et al. model with the drug docked in the configuration shown in the methods section. The complete structure in (A,B) shows the location of segment 6 (S6) lining the pore where key residues such as Y652 and F656 are located and the outer S5 segment where F557, a major residue of the side pocket, is located. The selectivity SF was also annotated where T623 and S624 sit at the base of the pore helix attached to it. Lopinavir is represented as a space-filling structure. Major amino acid constituents of the binding sites were shown as sticks. Binding residues and atoms of the drug molecule colored as for Figure 1. (A,B) show low-energy-score pose for lopinavir docked into the hERG pore with docking biased to promote occupation of the canonical binding site. (A) shows the lopinavir docking in the hERG cryo-EM structure. (B) shows the lopinavir docking in the Dickson et al. model based on hERG cryo-EM structure. Annotations (dotted lines) define potential interactions between drug and amino acid side chains, distances in (A) between the drug molecule and key residues were written adjacent to each dotted line. This run in the Dickson et al. model is particularly important since rotamers of at least one of F656 side chains was selected to orient the side chain Cα-Cβ bond toward the pore.