Figure 1, Key figure. Major functional aspects of membrane transporters.

(A) Schematic representation of major conformational states visited by a membrane transporter during the alternating access mechanism (see Box 1) as it facilitates the substrate and/or ion transport. Protein is represented by a white cartoon while the membrane by a brown disc. Ions and substrate are represented by yellow circle and blue hexagon, respectively. (B) Local conformational changes. A typical monomer of fully-bound glutamate transporter (Glt) with scaffold domain shown in pink and transport domain in blue. HP1 and HP2 loops which control the accessibility of the substrate binding site and therefore involved in gating, are shown in green. In the fully bound state (with 3 bound Na⁺ and the substrate), the transporter remains closed throughout the 500 ns of MD simulations (starting snapshots of HP1 and HP2 are shown in grey). MD simulations of the partially bound state (with two bound Na⁺ ions) captures the opening of HP2 gate, thus highlighting the importance of substrate and third Na⁺ in locking the extracellular gate of the transporter. (C) Global structural transition. Crystal and cryo-EM structures of ABC-transporter Pgp in IF (left, PDB: 4M1M) and OF (right, PDB: 6C0V) states, respectively. Pgp is a heterodimer comprising of two pseudosymetric halves (shown in blue and pink surface representations, respectively) each containing a transmembrane domain (TMD) connected to a nucleotide-binding domain (NBD). Binding of ATP (shown in van der Waals) to the NBDs leads to their dimerization and transition of the transporter from the IF to the OF state. The arrows depict the binding of the substrate molecule to the lumen in the IF state and its release to the extracellular side in the OF state, respectively. (D) Lipid-protein interactions. Crystal structure of ABC transporter MsbA (left, PDB: 5TV4), an inner membrane lipid flippase, reveals a lipopolysaccharide (LPS) molecule bound deeply in the cavity, shedding light on the mechanism of MsbA-mediated LPS transport. The two monomers of the transporter are shown as blue and pink cartoon representations, respectively. The bound LPS is shown as sticks. Crystal structure of dopamine transporter (DAT) (right, PDB: 4M48), a neurotransmitter transporter, reveals a cholesterol molecule bound at the junction of TM5 (blue) and TM7 (pink). The protein is drawn in cartoon representation, whereas the cholesterol and the coordinating residues are shown as sticks. (E) Drug-transporter interactions. Interaction of serotonin transporter (SERT) with paroxetine (left, PDB: 5I6X) and ibogaine (right, PDB: 6DZZ) in its different functional states, respectively. The drugs wedge between scaffold (pink) and core helices (blue), potentially interfering with their structural transition during the transporter function. The bound drugs and the extracellular gating residues are highlighted as sticks. The blue curves indicate the exposure of the central binding pocket.