Fig. 7: Ι Model of the pH-sensing mechanism of PfCRTDd2.
Upper panel. The carboxyl side chain of E207 is located at the periphery of the substrate binding cavity in the open-to-vacuole conformation, with the side chain protruding into the cavity space and, thus, being exposed to the environment. At the pH of 5.2 of the digestive vacuole, the carboxyl side chain is mostly deprotonated and, hence, negatively charged. However, some protonated species exist, which explains the reduced transport rate at pH 5.2 as compared with pH 6.2. During the transport cycle, E207 repositions from a peripheral to an engaged position, moving the negatively charged carboxyl side chain close to the positively charged amino group side chain of K80. The predicted close distance between these two residues of ~ 1.80 Å facilitates the formation of a salt bridge, which, in turn, accelerates progression through the transport cycle. Lower panel. Protonation of the carboxyl side chain of E207 at low pH values would preclude the formation of a salt bridge with K80. Instead, the protonated carboxyl side chain of E207 would hydrogen bond with the carboxyl group of E372. In addition, the additional proton might cause possible steric problems. As a result, the transport activity is reduced.
