National Natural Science Foundation of China (NSFC)
31971123
中国
National Natural Science Foundation of China (NSFC)
81920108015
中国
National Natural Science Foundation of China (NSFC)
31930059
中国
引用
ジャーナル: Cell Discov / 年: 2021 タイトル: Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter. 著者: Renhong Yan / Yaning Li / Jennifer Müller / Yuanyuan Zhang / Simon Singer / Lu Xia / Xinyue Zhong / Jürg Gertsch / Karl-Heinz Altmann / Qiang Zhou / 要旨: LAT1 (SLC7A5) is one of the representative light chain proteins of heteromeric amino acid transporters, forming a heterodimer with its heavy chain partner 4F2hc (SLC3A2). LAT1 is overexpressed in ...LAT1 (SLC7A5) is one of the representative light chain proteins of heteromeric amino acid transporters, forming a heterodimer with its heavy chain partner 4F2hc (SLC3A2). LAT1 is overexpressed in many types of tumors and mediates the transfer of drugs and hormones across the blood-brain barrier. Thus, LAT1 is considered as a drug target for cancer treatment and may be exploited for drug delivery into the brain. Here, we synthesized three potent inhibitors of human LAT1, which inhibit transport of leucine with IC values between 100 and 250 nM, and solved the cryo-EM structures of the corresponding LAT1-4F2hc complexes with these inhibitors bound at resolution of up to 2.7 or 2.8 Å. The protein assumes an outward-facing occluded conformation, with the inhibitors bound in the classical substrate binding pocket, but with their tails wedged between the substrate binding site and TM10 of LAT1. We also solved the complex structure of LAT1-4F2hc with 3,5-diiodo-L-tyrosine (Diiodo-Tyr) at 3.4 Å overall resolution, which revealed a different inhibition mechanism and might represent an intermediate conformation between the outward-facing occluded state mentioned above and the outward-open state. To our knowledge, this is the first time that the outward-facing conformation is revealed for the HAT family. Our results unveil more important insights into the working mechanisms of HATs and provide a structural basis for future drug design.
4F2cell-surfaceantigenheavychain / 4F2hc / Solute carrier family 3 (Activators of dibasic and neutral amino acid transport) / member 2 ...4F2hc / Solute carrier family 3 (Activators of dibasic and neutral amino acid transport) / member 2 / isoform CRA_a
分子量: 70160.828 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: SLC3A2, hCG_2016598 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: J3KPF3
#2: タンパク質
Largeneutralaminoacidstransportersmallsubunit1 / 4F2 light chain / 4F2LC / CD98 light chain / Integral membrane protein E16 / E16 / L-type amino ...4F2 light chain / 4F2LC / CD98 light chain / Integral membrane protein E16 / E16 / L-type amino acid transporter 1 / hLAT1 / Solute carrier family 7 member 5 / y+ system cationic amino acid transporter
分子量: 57186.895 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: SLC7A5, CD98LC, LAT1, MPE16 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: Q01650