2.A.41.2.6
Broad-specificity nucleoside:Na⁺, H⁺ and Li⁺ symporter, hCNT3 (Slc28a3) transports a broad range of both purine and pyrimidine nucleosides as well as anticancer and antiviral nucleoside drugs, but guanosine, 3'azido-3-deoxythymidine and 2',3'-dideoxycytidine, which are substrates with Na⁺, are not substrates with H⁺. Both of the two cation-binding sites can apparently bind Na⁺, but only one can bind H⁺, and the Na⁺ and H⁺ forms transport different ranges of substrates. (Note: Cnt1 and Cnt2 are Na⁺-specific.) (Smith et al., 2005).  (Na⁺/nucleoside = 2; Na⁺ + H⁺/nucleoside = 2; H⁺/nucleoside = 1).  The matricellular protein, cysteine-rich angiogenic inducer 61 (CYR61), negatively regulates synthesis of the nucleoside transporters hENT1 and hCNT3, both of which transport the anti-cancer agent, gemcitabine (Hesler et al. 2016). Also probably transports gemcitabine, 3'-azido-3'-deoxythymidine (AZT), ribavirin and 3-deazauridine. Modeling revealed mobility of selected binding site and homotrimer interface residues (Latek 2017). The 3-D structure has been solved at 3.6 Å resolution by cryoEM (Zhou et al. 2020). As for its bacterial homologs, hCNT3 presents a trimeric architecture with additional N-terminal transmembrane helices to stabilize the conserved central domains. The conserved binding sites for the substrate and sodium ions unravel the selective nucleoside transport and distinct coupling mechanism (Zhou et al. 2020). A multistep elevator-like transport mechanism for nucleoside transport has been proposed (Duan et al. 2021).