National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)
DK122784
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM145416
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
HL086392
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM098878
米国
Cancer Prevention and Research Institute of Texas (CPRIT)
R1223
米国
National Science Foundation (NSF, United States)
DMR-1420541
米国
引用
ジャーナル: Structure / 年: 2022 タイトル: Extracellular domain of PepT1 interacts with TM1 to facilitate substrate transport. 著者: Jiemin Shen / Miaohui Hu / Xiao Fan / Zhenning Ren / Corinne Portioli / Xiuwen Yan / Mingqiang Rong / Ming Zhou / 要旨: Mammalian peptide transporters, PepT1 and PepT2, mediate uptake of small peptides and are essential for their absorption. PepT also mediates absorption of many drugs and prodrugs to enhance their ...Mammalian peptide transporters, PepT1 and PepT2, mediate uptake of small peptides and are essential for their absorption. PepT also mediates absorption of many drugs and prodrugs to enhance their bioavailability. PepT has twelve transmembrane (TM) helices that fold into an N-terminal domain (NTD, TM1-6) and a C-terminal domain (CTD, TM7-12) and has a large extracellular domain (ECD) between TM9-10. It is well recognized that peptide transport requires movements of the NTD and CTD, but the role of the ECD in PepT1 remains unclear. Here we report the structure of horse PepT1 encircled in lipid nanodiscs and captured in the inward-open apo conformation. The structure shows that the ECD bridges the NTD and CTD by interacting with TM1. Deletion of ECD or mutations to the ECD-TM1 interface impairs the transport activity. These results demonstrate an important role of ECD in PepT1 and enhance our understanding of the transport mechanism in PepT1.