Figure 7.

Fit of the predicted most stable binding poses of MSR03 with a neutral or positively charged quinoline moiety in αVβ3 from induced-fit docking-metadynamics rescoring into the cryo-EM density map of MSR03-bound αVβ3. Cartoon representations of the αV and β3 chains of integrin αVβ3 shown in transparent orange and green colors, respectively. MSR03 is shown in cyan color for the predicted poses of the molecule with a neutral quinoline group simulated in the presence of the MIDAS metal ion (panels (A) and (B); same poses as poses #2 and #5 in Figure 3, respectively) or a positively charged quinoline group simulated in the absence of the MIDAS metal ion (panel (C), same pose as pose #1 in Figure 5). Cryo-EM density contoured at σ = 0.32 within 1.5 Å of the ligand is shown as a gray mesh and the density attributed to the MIDAS metal ion contoured at σ = 1.03 is colored in magenta. Shown in sticks are the side chains of the αV D218, β3 Y122, and β3 E220 residues. Distances between the tetrahydronaphthyridine group of MSR03 and the carboxyl oxygens of αV D218, as well as the quinoline group of MSR03 and the MIDAS metal ion (when the group is neutral) or a carboxyl oxygen of β E220 (when the group is positively charged), are indicated with dotted lines.