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. Author manuscript; available in PMC: 2019 May 31.
Published in final edited form as: J Phys Chem B. 2017 Dec 26;122(21):5336–5346. doi: 10.1021/acs.jpcb.7b10340

Figure 1.

Figure 1

Four major conformers visited during the transport cycle of hDAT, in the presence of lipid bilayer, and key residues implicated in EC gating, substrate binding, and IC gating. The panels illustrate the MD environment/snapshots for: (A) outward-facing open (OFo) state, with the substrate (DA; purple, space-filling) initially 15 Å away from substrate-binding site; (B) outward-facing open (OFo*) form with the DA bound to the S1 site; (C) DA-bound inward-facing open (IFo*), prior to translocation and release to the IC region; and (D) DA-free inward-facing open (IFo). The respective EC and IC gating pairs, R85-D476 and R60-D436, are shown in sticks. Note that the EC gates are open in (A) and (B), whereas the IC gates are closed; the opposite takes place in (C), and both gates are partially/completely closed in (D). hDAT also samples a holo occluded state,37 between (B) and (C), with the gates closed to both environments, not shown here. The POPC lipids are shown in green lines with P-atoms in tan spheres. Cyan and yellow spheres represent the co-transported Cl− and two Na+ ions, respectively.