Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties
Figure 3
Activation steps of 5-HT2AR bound with 5-HT.
(A) Evolution of the bend angle in TM6 around P6.50, highlighting the intervals during which the helix straightens (event 1) and bends (event 3) upon activation. (B) Evolution of the Cα distances between D3.32 and F6.52 (red), and between D3.32 and N6.55 (black), illustrating the interval during which the EC end of TM6 moves towards TM3 (event 2). (C) Evolution of the tilt angle of the toggle switch W6.48 aromatic ring with respect to the membrane normal, showing the time point of W6.48 flipping (event 4). W6.48 becomes parallel to the membrane for ∼1 ns at 143 ns (see panel J) with χ1 angle changing from g- to trans. (D) Evolution of the Cα distance between D3.32 and V6.40 illustrating the interval when the IC end of TM6 moves away from TM3 (event 5). (E) Dynamics of the ionic lock presented as the evolution of the Cα distance between R3.50 and E6.30. Initially broken ionic lock forms during the first 50 ns, before opening again upon activation at ∼170 ns (event 6). (F) Evolution of the Cα distance between Y7.53 and Y7.60. (G) Snapshots from the membrane plane and the EC end, highlighting positions of D3.32 and N6.55 and the distance between them, and showing the initial straightening and motion of TM6 towards TM3 (event 1). Gray cartoon represents the starting structure, and the orange cartoon is the structure averaged over the 83–112 ns interval. (H) Cartoon representation of TM3 and TM6 highlighting the kink in the TM6 that occurs in the 135–225 ns time interval (event 3). Orange and Magenta cartoons represent structures averaged over 83–112 ns and 290–350 ns, respectively. (I) Snapshots of TM3 and TM6 depicting positions of R3.50 and E6.30 residues and the distance between them and illustrating the movement of TM6 away from TM3 (event 5). Color code is the same as in panel G. (J) Detailed dynamics in the toggle switch W6.48. Evolution of the χ1 and χ2 angles is shown during the 140–146 ns time-interval when the toggle switch flips. Also shown are the snapshots at 0 ns and 143 ns time-points of the 5-HT and W6.48 (in spheres and colored by atom type, 5-HT in orange, and W6.48 in grey and cyan at 0 ns and 143 ns, respectively.).