Abstract
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. Peptide transporter 2 (PepT2) allows in addition renal drug reabsorption from ultrafiltration and brain-to-blood efflux of neurotoxic compounds. Here we present cryo-EM structures of human PepT1 in an outward open state and of human PepT2 in an inward facing partially occluded state with a bound substrate. The structures reveal the architecture of human peptide transporters and provide mechanistic insights into substrate recognition and conformational transitions during transport. Importantly, this may support future drug design efforts to increase the bioavailability of different drugs in the human body.
Competing Interest Statement
The authors have declared no competing interest.