2.A.41.2.8
Solute carrier family 28 member 3 (Concentrative Na⁺-nucleoside cotransporter 3) (CNT 3) (hCNT3).  This protein is distinct from TC# 2.A.41.2.6 (78% identity) although these two proteins are called Slc28a3 and CNT3 and have the same description in UniProt (see 2.A.41.2.6 for a more complete description).  hCNT3 can transport extracellular nucleosides and various nucleoside-derived anticancer drugs. Typical nucleoside anticancer drugs, including fludarabine, cladabine, decitabine, and clofarabine, are recognized by hCNT3 and then delivered to the lesion site for their therapeutic effects. hCNT3 is highly conserved during the evolution from lower to higher vertebrates, which contains scaffold and transport domains in structure and delivers substrates by coupling with Na⁺ and H⁺ ions in function. In the process of substrate delivery, the transport domain rises from the lower side of TMS9 in the inward conformation to the upper side of the outward conformation, accompanied by the collaborative motion of TMS7b/ TMS4b and hairpin 1b (HP1b)/HP2b. With the report of a series of three-dimensional structures of homologous CNTs, the structural characteristics and biological functions of hCNT3 hae become important. Yue et al. 2023 designed an anticancer lead compound with high hCNT3 transport potential based on the structure of 5-fluorouracil. The sequence evolution, conservation, molecular structure, cationic chelation, substrate recognition, elevator motion pattern and nucleoside derivative drugs of hCNT3 were reviewed, and the differences in hCNT3 transport mode and nucleoside anticancer drug modification were summarized (Yue et al. 2023).  The conformational trajectory of CNT3 during membrane transport of a nucleoside analog antiviral drug has been considered (Wright et al. 2024).