Conformational flexibility of the MmpL3 transporter.

(a) Superimposition of the 7 structures of MmpL3. The structures indicate that PD2 is able to perform a rigid body rotational motion, transitioning from one conformational state to the other. The transmembrane helices, particularly TM7–TM12, are also found to shift their locations, accompanying the rotational motion of PD2. (b) MD simulations of the MmpL3 transporter. Consistent with the 7 structures of MmpL3, the first eigenvector based on PCA suggests that the major motion of MmpL3 is the rigid body rotation of the PD2 subdomain. (c and d) The 2 flexible loops 423–426 and 523–525 create the narrowest region of the channel. These residues may be important for controlling the (c) closing and (d) opening of this channel by coupling with the dynamic motion of the periplasmic subdomain PD2. Residues S423, L424, R523, N524, and D525 are indicated as green sticks. MD, molecular dynamics; MmpL3, mycobacterial membrane protein large 3; PCA, principal component analysis.