Extended Data Fig. 9 |. Model for ligand-induced closure of the extracellular gate.

a, Structure of PCFT highlighting the extracellular gate helices, TM7 and TM8 (red) and their relationship to the bound pemetrexed molecule (yellow). The arrow indicates the movement required to seal the binding site from the extracellular side of the membrane. The interaction of Phe290 with the benzyl group of pemetrexed is likely to have an important role in triggering gate closure. b, Structural comparison between the apo and pemetrexed-bound states reveals repositioning of His289, resulting in the breakage of its interaction with Asn350 and facilitating the movement of TM7. The water pocket substantially enlarges in the pemetrexed-bound state, consistent with greater flexibility in the C-terminal bundle under acidic conditions.