Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter

• DOI: 10.1038/s41421-021-00247-4
• Publication Date: 2021-03-23T19:03:36Z
• Authors: Renhong Yan; Yaning Li; Jennifer Müller; Yuanyuan Zhang; Simon Singer; Lu Xia; Xinyue Zhong; Jürg Gertsch; Karl-Heinz Altmann; Qiang Zhou
• Keywords: Cryoelectron microscopy; Mechanisms of disease; Mechanisms of disease; QH573-671; Cryoelectron microscopy; 570 Life sciences; biology; 610 Medicine & health; Cytology; Article; 3. Good health

Abstract LAT1 (SLC7A5) is one of the representative light chain proteins heteromeric amino acid transporters, forming a heterodimer with its heavy partner 4F2hc (SLC3A2). overexpressed in many types tumors and mediates transfer drugs hormones across blood-brain barrier. Thus, considered as drug target for cancer treatment may be exploited delivery into brain. Here, we synthesized three potent inhibitors human LAT1, which inhibit transport leucine IC 50 values between 100 250 nM, solved cryo-EM structures corresponding LAT1-4F2hc complexes these bound at resolution up to 2.7 or 2.8 Å. The protein assumes an outward-facing occluded conformation, classical substrate binding pocket, but their tails wedged site TM10 LAT1. We also complex structure 3,5-diiodo- l -tyrosine (Diiodo-Tyr) 3.4 Å overall resolution, revealed different inhibition mechanism might represent intermediate conformation state mentioned above outward-open state. To our knowledge, this first time that HAT family. Our results unveil more important insights working mechanisms HATs provide structural basis future design.