Un-gating and allosteric modulation of a pentameric ligand-gated ion channel captured by molecular dynamics
Fig 7
An upward movement of the β1-β2 loop correlated with the twisting isomerization couples orthosteric agonist unbinding to pore closing in GluCl.
On the left, the correlation between the vertical separation of the β1-β2 loop from the M2-M3 loop (ΔZ) with the twisting angle (τ) and the cross section of the pore at the constriction point are shown. ΔZ is computed as the distance, projected on the Z axis, between the α-carbons of residues P268 (on M2-M3 loop) and V45 (on β1-β2 loop) averaged over the 5 subunits. The isocontour lines correspond to the simulations of GluCl active (red) and resting (green). The color gradient from red to green illustrates the time evolution of GluCl active with IVM removed. On the right, the gating mechanism is illustrated using snapshots taken at the beginning (red) and the end (blue) of the MD relaxation. Upon L-Glu unbinding, global receptor twisting results in an upward movement of the β1-β2 loop that facilitates the passage of the bulky proline 268 at the EC/TM interface to shut the pore at position 9′.