Killer Maxime, Wald Jiri, Pieprzyk Joanna, Marlovits Thomas C, Löw Christian
Centre for Structural Systems Biology (CSSB), Notkestrasse 85, D-22607 Hamburg, Germany.
European Molecular Biology Laboratory (EMBL), Hamburg Unit c/o Deutsches Elektronen Synchrotron (DESY), Notkestrasse 85, D-22607 Hamburg, Germany.
Sci Adv. 2021 Nov 5;7(45):eabk3259. doi: 10.1126/sciadv.abk3259. Epub 2021 Nov 3.
The uptake of peptides in mammals plays a crucial role in nutrition and inflammatory diseases. This process is mediated by promiscuous transporters of the solute carrier family 15, which form part of the major facilitator superfamily. Besides the uptake of short peptides, peptide transporter 1 (PepT1) is a highly abundant drug transporter in the intestine and represents a major route for oral drug delivery. PepT2 also allows renal drug reabsorption from ultrafiltration and brain-to-blood efflux of neurotoxic compounds. Here, we present cryogenic electron microscopy (cryo-EM) structures of human PepT1 and PepT2 captured in four different states throughout the transport cycle. The structures reveal the architecture of human peptide transporters and provide mechanistic insights into substrate recognition and conformational transitions during transport. This may support future drug design efforts to increase the bioavailability of different drugs in the human body.
哺乳动物中肽的摄取在营养和炎症性疾病中起着至关重要的作用。这一过程由溶质载体家族15的多特异性转运蛋白介导，该家族是主要转运体超家族的一部分。除了摄取短肽外，肽转运蛋白1（PepT1）是肠道中高度丰富的药物转运蛋白，是口服给药的主要途径。PepT2还允许从超滤中进行肾脏药物重吸收以及神经毒性化合物从脑到血的外排。在此，我们展示了在整个转运循环中处于四种不同状态下捕获的人PepT1和PepT2的低温电子显微镜（cryo-EM）结构。这些结构揭示了人肽转运蛋白的结构，并为转运过程中的底物识别和构象转变提供了机制见解。这可能有助于未来的药物设计工作，以提高不同药物在人体内的生物利用度。
